Activity

Filter

Cancel
Date Panel Item Activity
187 actions
Nephrocalcinosis or nephrolithiasis v2.24 MOCOS Eleanor Williams Tag Q3_21_NHS_review tag was added to gene: MOCOS.
Nephrocalcinosis or nephrolithiasis v2.24 MOCOS Eleanor Williams Classified gene: MOCOS as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v2.24 MOCOS Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, with a recommendation for green rating following GMS review. 2 cases where urolithiasis is part of the Xanthinuria type 2 phenotype. Additional evidence from animal models.
Nephrocalcinosis or nephrolithiasis v2.24 MOCOS Eleanor Williams Gene: mocos has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v2.23 MOCOS Eleanor Williams Phenotypes for gene: MOCOS were changed from Xanthinuria type II (MIM603592) to Xanthinuria, type II, OMIM:603592
Nephrocalcinosis or nephrolithiasis v2.22 MOCOS Eleanor Williams Publications for gene: MOCOS were set to PMID: 11302742; 17368066; 14624414; 25967871; 34356852; 32073534; 30758870; 27919260
Nephrocalcinosis or nephrolithiasis v2.21 MOCOS Eleanor Williams Tag Q3_21_rating tag was added to gene: MOCOS.
Nephrocalcinosis or nephrolithiasis v2.21 MOCOS Eleanor Williams reviewed gene: MOCOS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Xanthinuria, type II, OMIM:603592; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v2.21 MOCOS Detlef Bockenhauer gene: MOCOS was added
gene: MOCOS was added to Nephrocalcinosis or nephrolithiasis. Sources: Literature
Mode of inheritance for gene: MOCOS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MOCOS were set to PMID: 11302742; 17368066; 14624414; 25967871; 34356852; 32073534; 30758870; 27919260
Phenotypes for gene: MOCOS were set to Xanthinuria type II (MIM603592)
Penetrance for gene: MOCOS were set to Incomplete
Review for gene: MOCOS was set to GREEN
Added comment: This gene had not been previously included in this panel, but there is good evidence from several publications that recessive loss-of-function variants in MOCOS are associated with Xanthinuria type 2. There is also a good pathophysiologic basis: MOCOS encodes a necessary co-factor for the 2 enzymes that degrade Xanthine, XDH and AOX1.
Moreover, there are spontaneous animal models, with MOCOS variants identified in a goat (PMID 30758870) and Tyrolean grey cattle (PMID 27919260).
Sources: Literature
Nephrocalcinosis or nephrolithiasis v2.21 ATP6V0A4 Arina Puzriakova Publications for gene: ATP6V0A4 were set to
Nephrocalcinosis or nephrolithiasis v2.20 ATP6V0A4 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: ATP6V0A4.
Tag watchlist_moi tag was added to gene: ATP6V0A4.
Nephrocalcinosis or nephrolithiasis v2.20 ATP6V0A4 Arina Puzriakova Added comment: Comment on mode of inheritance: Literature search showed that a single Japanese individual was reported in 2016 (PMID: 27274828) with a supposedly pathogenic heterozygous variant p.S544L. Hypokalemia, nephrocalcinosis and alkaluria suggesting distal renal tubular acidosis (dRTA) were detected, but metabolic acidosis was not evident. In 2020, a second Han Chinese family with five dRTA patients was reported (PMID: 32123165) who harboured the same p.S544L heterozygous variant. Some patients in this family were more severely affected than the previous case, displaying more severe complete dRTA with hypokalemia, osteoporosis, and kidney stones. Note this family also harboured 3 other homozygous variants in the ATP6V0A4 gene but these were ruled out, presumably due to MAF.

Apart from these two reports’ alternations in ATP6V0A4 have been found to be inherited recessively (heterozygous parent carriers are unaffected), and multiple such cases have been described in literature (references added to publications list).

At this moment there is only enough evidence to support an Amber rating for the monoallelic form - single heterozygous variant identified in 2 families from a similar ethnic background which does not suffice the inclusion criteria.

MOI should be changed from 'BOTH mono- and biallelic' to 'BIALLELIC' only at the next GMS panel review (tagged) until additional evidence emerges supporting heterozygous variants as disease-causing.
Nephrocalcinosis or nephrolithiasis v2.20 ATP6V0A4 Arina Puzriakova Mode of inheritance for gene: ATP6V0A4 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v2.19 ATP6V0A4 Arina Puzriakova Phenotypes for gene: ATP6V0A4 were changed from distal renal tubular acidosis; Compensated or uncomensated dRTA and/or recurrent stone formation, usually with hypocitraturia. +/- deafness; Renal tubular acidosis, distal, autosomal recessive to Distal renal tubular acidosis 3, with or without sensorineural hearing loss, OMIM:602722
Nephrocalcinosis or nephrolithiasis v2.18 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from Lowe syndrome, 309000; Dent disease 2, 300555; As for CLCN5 (Nephrocalcinosis with low molecular weight proteinuria and pregressive CKD) but may include intellectual disability and other features of Lowe syndrome to Lowe syndrome, OMIM:309000; Dent disease 2, OMIM:300555; As for CLCN5 (Nephrocalcinosis with low molecular weight proteinuria and pregressive CKD) but may include intellectual disability and other features of Lowe syndrome
Nephrocalcinosis or nephrolithiasis v2.17 OCRL Eleanor Williams Publications for gene: OCRL were set to
Nephrocalcinosis or nephrolithiasis v2.16 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Nephrocalcinosis or nephrolithiasis v2.16 VIPAS39 Arina Puzriakova Classified gene: VIPAS39 as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v2.16 VIPAS39 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Nephrocalcinosis or nephrolithiasis v2.16 VIPAS39 Arina Puzriakova Gene: vipas39 has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v2.15 VIPAS39 Arina Puzriakova Tag for-review tag was added to gene: VIPAS39.
Nephrocalcinosis or nephrolithiasis v2.15 VPS33B Arina Puzriakova Classified gene: VPS33B as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v2.15 VPS33B Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Nephrocalcinosis or nephrolithiasis v2.15 VPS33B Arina Puzriakova Gene: vps33b has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v2.14 VPS33B Arina Puzriakova Tag for-review tag was added to gene: VPS33B.
Nephrocalcinosis or nephrolithiasis v2.14 HNF4A Arina Puzriakova Classified gene: HNF4A as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v2.14 HNF4A Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Nephrocalcinosis or nephrolithiasis v2.14 HNF4A Arina Puzriakova Gene: hnf4a has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v2.13 HNF4A Eleanor Williams Tag for-review tag was added to gene: HNF4A.
Nephrocalcinosis or nephrolithiasis v2.13 VPS33B Rebecca Foulger Classified gene: VPS33B as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v2.13 VPS33B Rebecca Foulger Gene: vps33b has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v2.12 VPS33B Rebecca Foulger gene: VPS33B was added
gene: VPS33B was added to Nephrocalcinosis or nephrolithiasis. Sources: Literature
Mode of inheritance for gene: VPS33B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS33B were set to 15052268; 22753090
Phenotypes for gene: VPS33B were set to Arthrogryposis, renal dysfunction, and cholestasis 1, 208085
Added comment: Added to panel as Green gene as advised by Helen Brittain, Genomics England Clinical Team. This rating should be reviewed by GLHs at the date of next GMS panel update. ARC phenotype (MIM:208085) is appropriate for the panel, and sufficient cases to support causation (see also the other ARC gene, VIPAS39).
Sources: Literature
Nephrocalcinosis or nephrolithiasis v2.11 VIPAS39 Rebecca Foulger Classified gene: VIPAS39 as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v2.11 VIPAS39 Rebecca Foulger Gene: vipas39 has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v2.10 VIPAS39 Rebecca Foulger commented on gene: VIPAS39: PMID:20190753 (Cullinane et al., 2010) identify biallelic (homozygous or compound het) variants in 7 probands from consanguineous families with ARC (MIM:613404) from various ethnic backgrounds (Turkish, Croation, Israeli Arab, Italian). Variants include Q179X, T250ArgfsX279, R220X, Q291X, M1R. The paper does not further discuss the kidney phenotype.
Nephrocalcinosis or nephrolithiasis v2.10 VIPAS39 Rebecca Foulger gene: VIPAS39 was added
gene: VIPAS39 was added to Nephrocalcinosis or nephrolithiasis. Sources: Literature
Mode of inheritance for gene: VIPAS39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VIPAS39 were set to 20190753
Phenotypes for gene: VIPAS39 were set to Arthrogryposis, renal dysfunction, and cholestasis 2, 613404
Added comment: Added to panel as Green following advice from Helen Brittain, Genomics England Clinical Team. Nephrocalcinosis is a feature of the phenotype. Other syndromes are on this panel (Lesch-Nyhan and Lowe syndrome) as Green, and therefore rated Green to match. This rating should be reviewed by GLHs at the date of next GMS panel update.
Sources: Literature
Nephrocalcinosis or nephrolithiasis v2.9 SLC26A1 Eleanor Williams Publications for gene: SLC26A1 were set to 27210743; 20160351; 30383413; 27125215
Nephrocalcinosis or nephrolithiasis v2.8 SLC26A1 Eleanor Williams Publications for gene: SLC26A1 were set to 27210743; 27210743; 20160351; 30383413; 27125215
Nephrocalcinosis or nephrolithiasis v2.7 SLC26A1 Eleanor Williams Publications for gene: SLC26A1 were set to 27210743; 27210743; 20160351
Nephrocalcinosis or nephrolithiasis v2.6 SLC26A1 Eleanor Williams Classified gene: SLC26A1 as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v2.6 SLC26A1 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to amber. Although there are several reported cases there is also evidence that the reported variants are not causative.
Nephrocalcinosis or nephrolithiasis v2.6 SLC26A1 Eleanor Williams Gene: slc26a1 has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v2.5 SLC26A1 Eleanor Williams Classified gene: SLC26A1 as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v2.5 SLC26A1 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to amber. Although there are several reported cases there is also evidence that the reported variants are not causative.
Nephrocalcinosis or nephrolithiasis v2.5 SLC26A1 Eleanor Williams Gene: slc26a1 has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v2.4 SLC26A1 Eleanor Williams changed review comment from: Provisionally associated with ?Nephrolithiasis, calcium oxalate #167030 (AR) in OMIM.

PMID: 30383413 - Whittamore et al 2019 - were unable to were unable to reproduce the hyperoxaluria, hyperoxalemia, and urolithiasis of the original SAT-1-KO mouse model.

PMID: 27125215 - Wu et al 2016 - report that Human SLC26A1-mediated anion exchange differs from that of its rodent orthologs. Also using Xenopus oocytes they find that the C41W, A56T (also reported by Gee et al) variants found in a Mexican child with recessive proximal tubular Fanconi Syndrome and the Q566R and M132T variants from Dawson et al 2013 did not alter the functional properties tested of SLC26A1 and so the proposal that these are pathogenic variants for Renal Fanconi Syndrome disease or nephrolithiasis is NOT supported.

PMID: 27210743 - Gee et al 2016 - report 2 unrelated individuals. Case 1 - individual of Macedonian descent (A3054-21) who is from non-consanguineous parents and clinically presented with acute renal failure due to bilateral obstructive calculi, nephrocalcinosis, and bilateral ureteropelvic junction obstruction. Two compound heterozygous missense mutations (c.554C>T, p.Thr185Met and c.1073C>T, p.Ser358Leu) in SLC26A1 are reported. They have minor allele freq below 0.0006 in dbSNP. Case 2 - European-American boy (B641-12) who had nephrolithiasis and was born to consanguineous parents. A homozygous missense mutation (c.166G>A, p.Ala56Thr) in SLC26A1 was found. Its minor allele frequency is 0.0002 in dbSNP.

PMID: 24250268 - Dawson et al 2013 - screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis. Found one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The Q556R variant is found at a high allele frequency (0.3484 in NCBI).

PMID: 20160351 - Dawson et al 2010 - Sat1-/- mice (SLC26A1) exhibited hyperoxaluria with hyperoxalemia, nephrocalcinosis, and calcium oxalate stones in their renal tubules and bladder.

Summary:
Although there are 3+ cases (2 biallelic in Gee et al, 3 monalleleic and 2 biallelic in Dawson et al 2013), plus a mouse model (Dawson et all 2010), the high minor allele frequency of the Q556R variant and the lack of altered function in protein with the A56T and M132T variants (Wu et al), and the lack of reproducibility of the mouse model phenotype cast doubt on the causative role of these variants. Therefore this gene should be rated amber until more evidence for their role in nephrocalcinosis can be established.; to: Provisionally associated with ?Nephrolithiasis, calcium oxalate #167030 (AR) in OMIM.

PMID: 30383413 - Whittamore et al 2019 - were unable to reproduce the hyperoxaluria, hyperoxalemia, and urolithiasis of the original SAT-1-KO mouse model.

PMID: 27125215 - Wu et al 2016 - report that Human SLC26A1-mediated anion exchange differs from that of its rodent orthologs. Also using Xenopus oocytes they find that the C41W, A56T (also reported by Gee et al) variants found in a Mexican child with recessive proximal tubular Fanconi Syndrome and the Q566R and M132T variants from Dawson et al 2013 did not alter the functional properties tested of SLC26A1 and so the proposal that these are pathogenic variants for Renal Fanconi Syndrome disease or nephrolithiasis is NOT supported.

PMID: 27210743 - Gee et al 2016 - report 2 unrelated individuals. Case 1 - individual of Macedonian descent (A3054-21) who is from non-consanguineous parents and clinically presented with acute renal failure due to bilateral obstructive calculi, nephrocalcinosis, and bilateral ureteropelvic junction obstruction. Two compound heterozygous missense mutations (c.554C>T, p.Thr185Met and c.1073C>T, p.Ser358Leu) in SLC26A1 are reported. They have minor allele freq below 0.0006 in dbSNP. Case 2 - European-American boy (B641-12) who had nephrolithiasis and was born to consanguineous parents. A homozygous missense mutation (c.166G>A, p.Ala56Thr) in SLC26A1 was found. Its minor allele frequency is 0.0002 in dbSNP.

PMID: 24250268 - Dawson et al 2013 - screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis. Found one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The Q556R variant is found at a high allele frequency (0.3484 in NCBI).

PMID: 20160351 - Dawson et al 2010 - Sat1-/- mice (SLC26A1) exhibited hyperoxaluria with hyperoxalemia, nephrocalcinosis, and calcium oxalate stones in their renal tubules and bladder.

Summary:
Although there are 3+ cases (2 biallelic in Gee et al, 3 monalleleic and 2 biallelic in Dawson et al 2013), plus a mouse model (Dawson et all 2010), the high minor allele frequency of the Q556R variant and the lack of altered function in protein with the A56T and M132T variants (Wu et al), and the lack of reproducibility of the mouse model phenotype cast doubt on the causative role of these variants. Therefore this gene should be rated amber until more evidence for their role in nephrocalcinosis can be established.
Nephrocalcinosis or nephrolithiasis v2.4 SLC26A1 Eleanor Williams changed review comment from: Provisionally associated with ?Nephrolithiasis, calcium oxalate #167030 (AR) in OMIM.

PMID: 27125215 - Wu et al 2016 - report that Human SLC26A1-mediated anion exchange differs from that of its rodent orthologs. Also using Xenopus oocytes they find that the C41W, A56T (also reported by Gee et al) variants found in a Mexican child with recessive proximal tubular Fanconi Syndrome and the Q566R and M132T variants from Dawson et al 2013 did not alter the functional properties tested of SLC26A1 and so the proposal that these are pathogenic variants for Renal Fanconi Syndrome disease or nephrolithiasis is NOT supported.

PMID: 27210743 - Gee et al 2016 - report 2 unrelated individuals. Case 1 - individual of Macedonian descent (A3054-21) who is from non-consanguineous parents and clinically presented with acute renal failure due to bilateral obstructive calculi, nephrocalcinosis, and bilateral ureteropelvic junction obstruction. Two compound heterozygous missense mutations (c.554C>T, p.Thr185Met and c.1073C>T, p.Ser358Leu) in SLC26A1 are reported. They have minor allele freq below 0.0006 in dbSNP. Case 2 - European-American boy (B641-12) who had nephrolithiasis and was born to consanguineous parents. A homozygous missense mutation (c.166G>A, p.Ala56Thr) in SLC26A1 was found. Its minor allele frequency is 0.0002 in dbSNP.

PMID: 24250268 - Dawson et al 2013 - screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis. Found one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The Q556R variant is found at a high allele frequency (0.3484 in NCBI).

PMID: 20160351 - Dawson et al 2010 - Sat1-/- mice (SLC26A1) exhibited hyperoxaluria with hyperoxalemia, nephrocalcinosis, and calcium oxalate stones in their renal tubules and bladder.

Summary:
Although there are 3+ cases (2 biallelic in Gee et al, 3 monalleleic and 2 biallelic in Dawson et al 2013), plus a mouse model (Dawson et all 2010), the minor allele frequency of the Q556R variant and the lack of altered function for when protein with the A56T and M132T variants are expressed (Wu et al) cast doubt on the causative role of these variants. Therefore this gene should be rated amber until more evidence for their role in nephrocalcinosis can be established.; to: Provisionally associated with ?Nephrolithiasis, calcium oxalate #167030 (AR) in OMIM.

PMID: 30383413 - Whittamore et al 2019 - were unable to were unable to reproduce the hyperoxaluria, hyperoxalemia, and urolithiasis of the original SAT-1-KO mouse model.

PMID: 27125215 - Wu et al 2016 - report that Human SLC26A1-mediated anion exchange differs from that of its rodent orthologs. Also using Xenopus oocytes they find that the C41W, A56T (also reported by Gee et al) variants found in a Mexican child with recessive proximal tubular Fanconi Syndrome and the Q566R and M132T variants from Dawson et al 2013 did not alter the functional properties tested of SLC26A1 and so the proposal that these are pathogenic variants for Renal Fanconi Syndrome disease or nephrolithiasis is NOT supported.

PMID: 27210743 - Gee et al 2016 - report 2 unrelated individuals. Case 1 - individual of Macedonian descent (A3054-21) who is from non-consanguineous parents and clinically presented with acute renal failure due to bilateral obstructive calculi, nephrocalcinosis, and bilateral ureteropelvic junction obstruction. Two compound heterozygous missense mutations (c.554C>T, p.Thr185Met and c.1073C>T, p.Ser358Leu) in SLC26A1 are reported. They have minor allele freq below 0.0006 in dbSNP. Case 2 - European-American boy (B641-12) who had nephrolithiasis and was born to consanguineous parents. A homozygous missense mutation (c.166G>A, p.Ala56Thr) in SLC26A1 was found. Its minor allele frequency is 0.0002 in dbSNP.

PMID: 24250268 - Dawson et al 2013 - screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis. Found one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The Q556R variant is found at a high allele frequency (0.3484 in NCBI).

PMID: 20160351 - Dawson et al 2010 - Sat1-/- mice (SLC26A1) exhibited hyperoxaluria with hyperoxalemia, nephrocalcinosis, and calcium oxalate stones in their renal tubules and bladder.

Summary:
Although there are 3+ cases (2 biallelic in Gee et al, 3 monalleleic and 2 biallelic in Dawson et al 2013), plus a mouse model (Dawson et all 2010), the high minor allele frequency of the Q556R variant and the lack of altered function in protein with the A56T and M132T variants (Wu et al), and the lack of reproducibility of the mouse model phenotype cast doubt on the causative role of these variants. Therefore this gene should be rated amber until more evidence for their role in nephrocalcinosis can be established.
Nephrocalcinosis or nephrolithiasis v2.4 SLC26A1 Eleanor Williams commented on gene: SLC26A1
Nephrocalcinosis or nephrolithiasis v2.4 HNF4A Eleanor Williams Classified gene: HNF4A as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v2.4 HNF4A Eleanor Williams Added comment: Comment on list classification: Although only one variant reported in all cases, there are now 7 cases in which the R76W/R63W (depending on reference transcript used) variant has been found in patients with Fanconi renotubular syndrome and nephrocalcinosis is a feature. Fly model also supports a pathogenic role for this variant.
Nephrocalcinosis or nephrolithiasis v2.4 HNF4A Eleanor Williams Gene: hnf4a has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v2.3 HNF4A Eleanor Williams changed review comment from: Note the same codon is reported as R76W and R63W in different paper depending on whether NM_000457 or NM_175914 is used as the reference transcript.

Additional papers including those cited by Zornitza Stark:

PMID: 31875549 - Marchesin et al 2019 - Fly model which shows that the R85W variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect. Expression of dHNF4 harboring the FRTS mutation affects the catabolism of lipid droplets in nephrocytes by interfering with mitochondrial function. They also showed that the FRTS mutation caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. The cytosolic aggregates have a cytotoxic affect. By contrast, the expression of another known close mutation in the DNA-binding domain, R89W (that leads to MODY1 but not to FRTS; Hamilton et al., 2014), did not cause any dominant-negative or cytotoxic effects.

PMID: 30005691 - Liu et al 2018 1 case of a 10-year-old girl of Chinese Han ethnicity who presented with renal Fanconi syndrome, infantile hyperinsulinemic hypoglycemia, and transient cholestasis. In addition, she presented with bilateral severe hearing loss. Renal ultrasonography showed nephrocalcinosis. Gene analysis showed a heterozygous p.R63W mutation in the HNF4A gene that is responsible for Fanconi syndrome and hyperinsulinemic hypoglycemia. (NOTE: no transcript identifier given but they refer to this as the same variant as R76W).

PMID: 28693455 - Walsh et al 2917 - 1 case of mother and son with heterozygous c.187C > T; p.Arg63Trp in HNF4A and Renal Fanconi syndrome. Mother is reported to have mild nephrocalcinosis

PMID: 22802087 - Stanescu et al 2012 - 1 case that presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Sequencing of HNF4A (MODY1) revealed a missense, de novo mutation (p.Arg76Trp, c.226C→T), (NM_000457) which is a known disease-causing MODY1 mutation in HNF4A. Nephrocalcinosis not specifically mentioned.

No nephrocalcinosis reported:
PMID: 28458902 - Clemente et al 2017 - 1 patient with congenital hyperinsulinaemic hypoglycaemia, rickets with craniotabes, wrist widening, genu varum and motor impairment. non-gap metabolic acidosis with acidified urine suggestive of proximal tubular acidosis, glycosuria with generalised aminoaciduria and tubular type proteinuria. Says this patient did NOT have the same ‘atypical’ Fanconi syndrome with hypercalciuria with relative hypocalcaemia, hypermagnesaemia, nephrocalcinosis and renal impairment as the patients reported by Hamilton et al 2014. A de novo variant p.Arg63Trp, c.187C > T (reference sequence: NM_175914.4) was found.

PMID: 27245055 - Improda et al 2016 - 2 infants with the p.R63W mutation HNF4A with macrosomia and atypical Fanconi syndrome, in addition to hyperinsulinaemic hypoglycaemia. No nephrocalcinosis reported but this may be due to young age.
; to: Note the same codon is reported as R76W and R63W in different paper depending on whether NM_000457 or NM_175914 is used as the reference transcript.

Additional papers including those cited by Zornitza Stark:

PMID: 31875549 - Marchesin et al 2019 - Fly model which shows that the R85W variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect. Expression of dHNF4 harboring the FRTS mutation affects the catabolism of lipid droplets in nephrocytes by interfering with mitochondrial function. They also showed that the FRTS mutation caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. The cytosolic aggregates have a cytotoxic affect. By contrast, the expression of another known close mutation in the DNA-binding domain, R89W (that leads to MODY1 but not to FRTS; Hamilton et al., 2014), did not cause any dominant-negative or cytotoxic effects.

PMID: 31949432 - Anyiam et al 2019 - described patient with Renal Fanconi syndrome and R63W mutation through 3rd pregnancy. She had a history of progressive renal insufficiency, persistent proteinuria, nephrocalcinosis, and recurrent nephrolithiasis.

PMID: 30005691 - Liu et al 2018 1 case of a 10-year-old girl of Chinese Han ethnicity who presented with renal Fanconi syndrome, infantile hyperinsulinemic hypoglycemia, and transient cholestasis. In addition, she presented with bilateral severe hearing loss. Renal ultrasonography showed nephrocalcinosis. Gene analysis showed a heterozygous p.R63W mutation in the HNF4A gene that is responsible for Fanconi syndrome and hyperinsulinemic hypoglycemia. (NOTE: no transcript identifier given but they refer to this as the same variant as R76W).

PMID: 28693455 - Walsh et al 2917 - 1 case of mother and son with heterozygous c.187C > T; p.Arg63Trp in HNF4A and Renal Fanconi syndrome. Mother is reported to have mild nephrocalcinosis

PMID: 22802087 - Stanescu et al 2012 - 1 case that presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Sequencing of HNF4A (MODY1) revealed a missense, de novo mutation (p.Arg76Trp, c.226C→T), (NM_000457) which is a known disease-causing MODY1 mutation in HNF4A. Nephrocalcinosis not specifically mentioned.

No nephrocalcinosis reported:
PMID: 28458902 - Clemente et al 2017 - 1 patient with congenital hyperinsulinaemic hypoglycaemia, rickets with craniotabes, wrist widening, genu varum and motor impairment. non-gap metabolic acidosis with acidified urine suggestive of proximal tubular acidosis, glycosuria with generalised aminoaciduria and tubular type proteinuria. Says this patient did NOT have the same ‘atypical’ Fanconi syndrome with hypercalciuria with relative hypocalcaemia, hypermagnesaemia, nephrocalcinosis and renal impairment as the patients reported by Hamilton et al 2014. A de novo variant p.Arg63Trp, c.187C > T (reference sequence: NM_175914.4) was found.

PMID: 27245055 - Improda et al 2016 - 2 infants with the p.R63W mutation HNF4A with macrosomia and atypical Fanconi syndrome, in addition to hyperinsulinaemic hypoglycaemia. No nephrocalcinosis reported but this may be due to young age.
Nephrocalcinosis or nephrolithiasis v2.3 HNF4A Eleanor Williams changed review comment from: Summary
3 publications (Hamilton et al 2014, Lui et al 2018, Walsh et al 2017) report 6 cases of patients with R76W/R63W variants in which nephrocalcinosis is a feature. Fly model (Marchesin et al 2019) shows that the equivalent variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect.; to: Summary
4 publications (Hamilton et al 2014, Lui et al 2018, Walsh et al 2017, Anyiam et al 2019) report 7 cases of patients with R76W/R63W variants in which nephrocalcinosis is a feature. Fly model (Marchesin et al 2019) shows that the equivalent variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect.
Nephrocalcinosis or nephrolithiasis v2.3 HNF4A Eleanor Williams commented on gene: HNF4A: Summary
3 publications (Hamilton et al 2014, Lui et al 2018, Walsh et al 2017) report 6 cases of patients with R76W/R63W variants in which nephrocalcinosis is a feature. Fly model (Marchesin et al 2019) shows that the equivalent variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect.
Nephrocalcinosis or nephrolithiasis v2.3 HNF4A Eleanor Williams changed review comment from: Note the same codon is reported as R76W and R63W in different paper depending on whether NM_000457 or NM_175914 is used as the reference transcript.

Additional papers cited by Zornitza Stark:

PMID: 31875549 - Marchesin et al 2019 - Fly model which shows that the R85W variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect. Expression of dHNF4 harboring the FRTS mutation affects the catabolism of lipid droplets in nephrocytes by interfering with mitochondrial function. They also showed that the FRTS mutation caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. The cytosolic aggregates have a cytotoxic affect. By contrast, the expression of another known close mutation in the DNA-binding domain, R89W (that leads to MODY1 but not to FRTS; Hamilton et al., 2014), did not cause any dominant-negative or cytotoxic effects.

PMID: 30005691 - Liu et al 2018 1 case of a 10-year-old girl of Chinese Han ethnicity who presented with renal Fanconi syndrome, infantile hyperinsulinemic hypoglycemia, and transient cholestasis. In addition, she presented with bilateral severe hearing loss. Renal ultrasonography showed nephrocalcinosis. Gene analysis showed a heterozygous p.R63W mutation in the HNF4A gene that is responsible for Fanconi syndrome and hyperinsulinemic hypoglycemia. (NOTE: This seems to be the same codon as the R76W variant as the paper refers to it as such).


PMID: 22802087 - Stanescu et al 2012 - 1 case that presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Sequencing of HNF4A (MODY1) revealed a missense, de novo mutation (p.Arg76Trp, c.226C→T), (NM_000457) which is a known disease-causing MODY1 mutation in HNF4A. Nephrocalcinosis not specifically mentioned.

No nephrocalcinosis reported:
PMID: 28458902 - Clemente et al 2017 - 1 patient with congenital hyperinsulinaemic hypoglycaemia, rickets with craniotabes, wrist widening, genu varum and motor impairment. non-gap metabolic acidosis with acidified urine suggestive of proximal tubular acidosis, glycosuria with generalised aminoaciduria and tubular type proteinuria. Says this patient did NOT have the same ‘atypical’ Fanconi syndrome with hypercalciuria with relative hypocalcaemia, hypermagnesaemia, nephrocalcinosis and renal impairment as the patients reported by Hamilton et al 2014. A de novo variant p.Arg63Trp, c.187C > T (reference sequence: NM_175914.4) was found.
; to: Note the same codon is reported as R76W and R63W in different paper depending on whether NM_000457 or NM_175914 is used as the reference transcript.

Additional papers including those cited by Zornitza Stark:

PMID: 31875549 - Marchesin et al 2019 - Fly model which shows that the R85W variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect. Expression of dHNF4 harboring the FRTS mutation affects the catabolism of lipid droplets in nephrocytes by interfering with mitochondrial function. They also showed that the FRTS mutation caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. The cytosolic aggregates have a cytotoxic affect. By contrast, the expression of another known close mutation in the DNA-binding domain, R89W (that leads to MODY1 but not to FRTS; Hamilton et al., 2014), did not cause any dominant-negative or cytotoxic effects.

PMID: 30005691 - Liu et al 2018 1 case of a 10-year-old girl of Chinese Han ethnicity who presented with renal Fanconi syndrome, infantile hyperinsulinemic hypoglycemia, and transient cholestasis. In addition, she presented with bilateral severe hearing loss. Renal ultrasonography showed nephrocalcinosis. Gene analysis showed a heterozygous p.R63W mutation in the HNF4A gene that is responsible for Fanconi syndrome and hyperinsulinemic hypoglycemia. (NOTE: no transcript identifier given but they refer to this as the same variant as R76W).

PMID: 28693455 - Walsh et al 2917 - 1 case of mother and son with heterozygous c.187C > T; p.Arg63Trp in HNF4A and Renal Fanconi syndrome. Mother is reported to have mild nephrocalcinosis

PMID: 22802087 - Stanescu et al 2012 - 1 case that presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Sequencing of HNF4A (MODY1) revealed a missense, de novo mutation (p.Arg76Trp, c.226C→T), (NM_000457) which is a known disease-causing MODY1 mutation in HNF4A. Nephrocalcinosis not specifically mentioned.

No nephrocalcinosis reported:
PMID: 28458902 - Clemente et al 2017 - 1 patient with congenital hyperinsulinaemic hypoglycaemia, rickets with craniotabes, wrist widening, genu varum and motor impairment. non-gap metabolic acidosis with acidified urine suggestive of proximal tubular acidosis, glycosuria with generalised aminoaciduria and tubular type proteinuria. Says this patient did NOT have the same ‘atypical’ Fanconi syndrome with hypercalciuria with relative hypocalcaemia, hypermagnesaemia, nephrocalcinosis and renal impairment as the patients reported by Hamilton et al 2014. A de novo variant p.Arg63Trp, c.187C > T (reference sequence: NM_175914.4) was found.

PMID: 27245055 - Improda et al 2016 - 2 infants with the p.R63W mutation HNF4A with macrosomia and atypical Fanconi syndrome, in addition to hyperinsulinaemic hypoglycaemia. No nephrocalcinosis reported but this may be due to young age.
Nephrocalcinosis or nephrolithiasis v2.3 HNF4A Eleanor Williams changed review comment from: Additional papers cited by Zornitza Stark:

PMID: 31875549 - Marchesin et al 2019 - Fly model which shows that the R85W variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect. Expression of dHNF4 harboring the FRTS mutation affects the catabolism of lipid droplets in nephrocytes by interfering with mitochondrial function. They also showed that the FRTS mutation caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. The cytosolic aggregates have a cytotoxic affect. By contrast, the expression of another known close mutation in the DNA-binding domain, R89W (that leads to MODY1 but not to FRTS; Hamilton et al., 2014), did not cause any dominant-negative or cytotoxic effects.

PMID: 30005691 - Liu et al 2018 1 case of a 10-year-old girl of Chinese Han ethnicity who presented with renal Fanconi syndrome, infantile hyperinsulinemic hypoglycemia, and transient cholestasis. In addition, she presented with bilateral severe hearing loss. Gene analysis showed a heterozygous p.R63W mutation in the HNF4A gene that is responsible for Fanconi syndrome and hyperinsulinemic hypoglycemia.

PMID: 22802087 - Stanescu et al 2012 - 1 case that presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Sequencing of HNF4A (MODY1) revealed a missense, de novo mutation (p.Arg76Trp, c.226C→T) which is a known disease-causing MODY1 mutation in HNF4A.

PMID: 28458902 - to be finished
; to: Note the same codon is reported as R76W and R63W in different paper depending on whether NM_000457 or NM_175914 is used as the reference transcript.

Additional papers cited by Zornitza Stark:

PMID: 31875549 - Marchesin et al 2019 - Fly model which shows that the R85W variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect. Expression of dHNF4 harboring the FRTS mutation affects the catabolism of lipid droplets in nephrocytes by interfering with mitochondrial function. They also showed that the FRTS mutation caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. The cytosolic aggregates have a cytotoxic affect. By contrast, the expression of another known close mutation in the DNA-binding domain, R89W (that leads to MODY1 but not to FRTS; Hamilton et al., 2014), did not cause any dominant-negative or cytotoxic effects.

PMID: 30005691 - Liu et al 2018 1 case of a 10-year-old girl of Chinese Han ethnicity who presented with renal Fanconi syndrome, infantile hyperinsulinemic hypoglycemia, and transient cholestasis. In addition, she presented with bilateral severe hearing loss. Renal ultrasonography showed nephrocalcinosis. Gene analysis showed a heterozygous p.R63W mutation in the HNF4A gene that is responsible for Fanconi syndrome and hyperinsulinemic hypoglycemia. (NOTE: This seems to be the same codon as the R76W variant as the paper refers to it as such).


PMID: 22802087 - Stanescu et al 2012 - 1 case that presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Sequencing of HNF4A (MODY1) revealed a missense, de novo mutation (p.Arg76Trp, c.226C→T), (NM_000457) which is a known disease-causing MODY1 mutation in HNF4A. Nephrocalcinosis not specifically mentioned.

No nephrocalcinosis reported:
PMID: 28458902 - Clemente et al 2017 - 1 patient with congenital hyperinsulinaemic hypoglycaemia, rickets with craniotabes, wrist widening, genu varum and motor impairment. non-gap metabolic acidosis with acidified urine suggestive of proximal tubular acidosis, glycosuria with generalised aminoaciduria and tubular type proteinuria. Says this patient did NOT have the same ‘atypical’ Fanconi syndrome with hypercalciuria with relative hypocalcaemia, hypermagnesaemia, nephrocalcinosis and renal impairment as the patients reported by Hamilton et al 2014. A de novo variant p.Arg63Trp, c.187C > T (reference sequence: NM_175914.4) was found.
Nephrocalcinosis or nephrolithiasis v2.3 HNF4A Eleanor Williams changed review comment from: Additional papers cited by Zornitza Stark:

PMID: 31875549 - Marchesin et al 2019 - Fly model. Used Drosophila nephrocytes as a model for proximal tubules to study the function of HNF4A and the impact of the FRTS-associated R85W mutation. Expression of dHNF4 harboring the FRTS mutation affects the catabolism of lipid droplets in nephrocytes by interfering with mitochondrial function. They also showed that the FRTS mutation promotes the nuclear export of a wild-type reporter protein, thereby reducing transcriptional output in a dominant-negative manner and promoting the formation of cytotoxic dHNF4 aggregates in the cytosol.
Review to be continued.

PMID: 22802087
PMID: 30005691
PMID: 28458902; to: Additional papers cited by Zornitza Stark:

PMID: 31875549 - Marchesin et al 2019 - Fly model which shows that the R85W variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect. Expression of dHNF4 harboring the FRTS mutation affects the catabolism of lipid droplets in nephrocytes by interfering with mitochondrial function. They also showed that the FRTS mutation caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. The cytosolic aggregates have a cytotoxic affect. By contrast, the expression of another known close mutation in the DNA-binding domain, R89W (that leads to MODY1 but not to FRTS; Hamilton et al., 2014), did not cause any dominant-negative or cytotoxic effects.

PMID: 30005691 - Liu et al 2018 1 case of a 10-year-old girl of Chinese Han ethnicity who presented with renal Fanconi syndrome, infantile hyperinsulinemic hypoglycemia, and transient cholestasis. In addition, she presented with bilateral severe hearing loss. Gene analysis showed a heterozygous p.R63W mutation in the HNF4A gene that is responsible for Fanconi syndrome and hyperinsulinemic hypoglycemia.

PMID: 22802087 - Stanescu et al 2012 - 1 case that presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Sequencing of HNF4A (MODY1) revealed a missense, de novo mutation (p.Arg76Trp, c.226C→T) which is a known disease-causing MODY1 mutation in HNF4A.

PMID: 28458902 - to be finished
Nephrocalcinosis or nephrolithiasis v2.3 HNF4A Eleanor Williams commented on gene: HNF4A: Additional papers cited by Zornitza Stark:

PMID: 31875549 - Marchesin et al 2019 - Fly model. Used Drosophila nephrocytes as a model for proximal tubules to study the function of HNF4A and the impact of the FRTS-associated R85W mutation. Expression of dHNF4 harboring the FRTS mutation affects the catabolism of lipid droplets in nephrocytes by interfering with mitochondrial function. They also showed that the FRTS mutation promotes the nuclear export of a wild-type reporter protein, thereby reducing transcriptional output in a dominant-negative manner and promoting the formation of cytotoxic dHNF4 aggregates in the cytosol.
Review to be continued.

PMID: 22802087
PMID: 30005691
PMID: 28458902
Nephrocalcinosis or nephrolithiasis v2.3 Eleanor Williams Panel version has been signed off
Nephrocalcinosis or nephrolithiasis v2.2 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Nephrocalcinosis or nephrolithiasis v2.0 SLC26A1 Zornitza Stark gene: SLC26A1 was added
gene: SLC26A1 was added to Nephrocalcinosis or nephrolithiasis. Sources: Expert list
Mode of inheritance for gene: SLC26A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC26A1 were set to 27210743; 27210743; 20160351
Phenotypes for gene: SLC26A1 were set to Nephrolithiasis, calcium oxalate, MIM#167030
Review for gene: SLC26A1 was set to GREEN
gene: SLC26A1 was marked as current diagnostic
Added comment: Three unrelated families and a mouse model.
Sources: Expert list
Nephrocalcinosis or nephrolithiasis v2.0 HNF4A Zornitza Stark reviewed gene: HNF4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31875549, 24285859, 22802087, 30005691, 28458902; Phenotypes: Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM #616026; Mode of inheritance: None; Current diagnostic: yes
Nephrocalcinosis or nephrolithiasis v2.0 Eleanor Williams promoted panel to version 2.0
Nephrocalcinosis or nephrolithiasis v1.52 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease; GMS signed-off
Nephrocalcinosis or nephrolithiasis v1.51 SLC9A3R1 Eleanor Williams Classified gene: SLC9A3R1 as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v1.51 SLC9A3R1 Eleanor Williams Added comment: Comment on list classification: Changing the rating of this gene to Amber in light of the expert review that highlights that the proposed pathogenic variants are found at higher than expected frequency in the general population.
Nephrocalcinosis or nephrolithiasis v1.51 SLC9A3R1 Eleanor Williams Gene: slc9a3r1 has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v1.50 SLC9A3R1 Detlef Bockenhauer changed review comment from: In the original publication (PMID: 18784102 - Karim et al 2008), Karim et al examine 159 patients with either nephrolithiasis or bone demineralisation. They find variants in SLC9A3R1 in 4 patients from 3 families. These 3 variants are now listed in gnomAD with a combined frequency of just over 2%. Thus, the frequency of these variants in the patient cohort is essentially the same as in the general population.
Several publications subsequently report variants in this gene in cohorts with nephrolithiasis/calcinosis, but again essentially with either the same or even lower frequency as in the normal population:
1) Daga et al (Kidney Int. 2018 Jan;93(1):204-213. doi: 10.1016/j.kint.2017.06.025): 1 out of 51 families
2) Braun et al (Clin J Am Soc Nephrol. 2016 Apr 7;11(4):664-72. doi: 10.2215/CJN.07540715): 1 out of 143
3) Halbritter et al (J Am Soc Nephrol. 2015 Mar; 26(3): 543–551doi: 10.1681/ASN.2014040388): 2 out of 268

Thus, there are several lines of evidence arguing against SLC9A3R1 being a disease causing gene:
1) the frequency of variants in SLC9A3R in itself higher than expected for a dominant disease gene (3% combined frequency of missense and pLoF in gnomAD)
2) there are 231 missende variants in this gene listed in gnomAD versus 211.7 expected, based on gene length (Z=-0.48), thus the gene is not constrained against missense variants
3) the frequency of variants in patients with nephrolithiasis/calcinosis is essentially the same as in the general population

The clinical relevance of any variants identified in SLC9A3R1 is thus questionable.; to: In the original publication (PMID: 18784102 - Karim et al 2008), Karim et al examine 159 patients with either nephrolithiasis or bone demineralisation. They find variants in SLC9A3R1 in 4 patients from 3 families. These 3 variants are now listed in gnomAD with a combined frequency of just over 2%. Thus, the frequency of these variants in the patient cohort is essentially the same as in the general population.
Several publications subsequently report variants in this gene in cohorts with nephrolithiasis/calcinosis, but again essentially with either the same or even lower frequency as in the normal population:
1) Daga et al (Kidney Int. 2018 Jan;93(1):204-213. doi: 10.1016/j.kint.2017.06.025): 1 out of 51 families
2) Braun et al (Clin J Am Soc Nephrol. 2016 Apr 7;11(4):664-72. doi: 10.2215/CJN.07540715): 1 out of 143
3) Halbritter et al (J Am Soc Nephrol. 2015 Mar; 26(3): 543–551doi: 10.1681/ASN.2014040388): 2 out of 268

Thus, there are several lines of evidence arguing against SLC9A3R1 being a disease causing gene:
1) the frequency of variants in SLC9A3R in itself is higher than expected for a dominant disease gene (3% combined frequency of missense and pLoF in gnomAD)
2) there are 231 missense variants in this gene listed in gnomAD versus 211.7 expected, based on gene length (Z=-0.48), thus the gene is not constrained against missense variants
3) the frequency of variants in patients with nephrolithiasis/calcinosis is essentially the same as in the general population

The clinical relevance of any variants identified in SLC9A3R1 is thus questionable.
Nephrocalcinosis or nephrolithiasis v1.50 SLC9A3R1 Detlef Bockenhauer changed review comment from: In the original publication (PMID: 18784102 - Karim et al 2008), Karim et al examine 159 patients with either nephrolithiasis or bone demineralisation. they find variants in SLC9A3R1 in 4 patients from 3 families. These variants are now listed in gnomAD with a combined frequency of just over 2%. Thus, the frequency of these variants in the patient cohort is essentially the same as in the general population.
Several publications subsequently report variants in this gene in cohorts with nephrolithiasis/calcinosis, but again essentially with either the same or even lower frequency as in the normal population:
1) Daga et al (Kidney Int. 2018 Jan;93(1):204-213. doi: 10.1016/j.kint.2017.06.025): 1 out of 51 families
2) Braun et al (Clin J Am Soc Nephrol. 2016 Apr 7;11(4):664-72. doi: 10.2215/CJN.07540715): 1 out of 143
3) Halbritter et al (J Am Soc Nephrol. 2015 Mar; 26(3): 543–551doi: 10.1681/ASN.2014040388): 2 out of 268

Thus, not only is the frequency of variants in SLC9A3R in itself higher than expected for a dominant disease gene, but the frequency of variants in patients with nephrolithiasis/calcinosis is essentially the same as in the general population and the likelihood that they disease causing is thus very unlikely.; to: In the original publication (PMID: 18784102 - Karim et al 2008), Karim et al examine 159 patients with either nephrolithiasis or bone demineralisation. They find variants in SLC9A3R1 in 4 patients from 3 families. These 3 variants are now listed in gnomAD with a combined frequency of just over 2%. Thus, the frequency of these variants in the patient cohort is essentially the same as in the general population.
Several publications subsequently report variants in this gene in cohorts with nephrolithiasis/calcinosis, but again essentially with either the same or even lower frequency as in the normal population:
1) Daga et al (Kidney Int. 2018 Jan;93(1):204-213. doi: 10.1016/j.kint.2017.06.025): 1 out of 51 families
2) Braun et al (Clin J Am Soc Nephrol. 2016 Apr 7;11(4):664-72. doi: 10.2215/CJN.07540715): 1 out of 143
3) Halbritter et al (J Am Soc Nephrol. 2015 Mar; 26(3): 543–551doi: 10.1681/ASN.2014040388): 2 out of 268

Thus, there are several lines of evidence arguing against SLC9A3R1 being a disease causing gene:
1) the frequency of variants in SLC9A3R in itself higher than expected for a dominant disease gene (3% combined frequency of missense and pLoF in gnomAD)
2) there are 231 missende variants in this gene listed in gnomAD versus 211.7 expected, based on gene length (Z=-0.48), thus the gene is not constrained against missense variants
3) the frequency of variants in patients with nephrolithiasis/calcinosis is essentially the same as in the general population

The clinical relevance of any variants identified in SLC9A3R1 is thus questionable.
Nephrocalcinosis or nephrolithiasis v1.50 SLC9A3R1 Detlef Bockenhauer commented on gene: SLC9A3R1
Nephrocalcinosis or nephrolithiasis v1.50 SLC9A3R1 Eleanor Williams changed review comment from: Associated with Nephrolithiasis/osteoporosis, hypophosphatemic, 2 #612287 (AD) in OMIM. A previous name for SLC9A3R1 is NHERF1.

Evidence for association comes from PMID: 18784102 - Karim et al 2008 - sequencing of the coding region of NHERF1 in 92 patients who presented with either renal stones or bone demineralization, together with normal serum PTH concentrations and who had no evidence of any usual causes of these disorders (e.g., hyperparathyroidism, hyperthyroidism, or an increased FGF-23 plasma concentration). These were group 1 patients. They identified three distinct missense mutations in the NHERF1 gene in four unrelated patients from group 1 (328C->G, L110V; 458G->A, R153Q; 673G->A, E225K).

They also studied patients who did not have renal stones or bone demineralization (group 2) who were referred to the clinical investigation department for renal assessment before undergoing a potentially nephrotoxic treatment for psoriasis. One patient in group 2 had an NHERF1 mutation (L110V). This patient had a low TmP/GFR value.; to: Associated with Nephrolithiasis/osteoporosis, hypophosphatemic, 2 #612287 (AD) in OMIM. A previous name for SLC9A3R1 is NHERF1.

Evidence for association comes from PMID: 18784102 - Karim et al 2008 - sequencing of the coding region of NHERF1 in 92 patients who presented with either renal stones or bone demineralization, together with normal serum PTH concentrations and who had no evidence of any usual causes of these disorders (e.g., hyperparathyroidism, hyperthyroidism, or an increased FGF-23 plasma concentration). These were group 1 patients. They identified three distinct missense mutations in the NHERF1 gene in four unrelated patients from group 1 (328C->G, L110V; 458G->A, R153Q; 673G->A, E225K).

They also studied patients who did not have renal stones or bone demineralization (group 2) who were referred to the clinical investigation department for renal assessment before undergoing a potentially nephrotoxic treatment for psoriasis. One patient in group 2 had an NHERF1 mutation (L110V). This patient had a low TmP/GFR value.


PMID: 28893421 - Daga et al 2018 - performed WES in 65 individuals from 51 families with nephrolithiasis and/or a finding of nephrocalcinosis on renal ultrasound, who manifested before the age of 25 years. They found 1 individual with a heterozygous pathogenic variant in SLC9A3R1 (c.673G>A, p.E225K).
Nephrocalcinosis or nephrolithiasis v1.50 SLC9A3R1 Eleanor Williams commented on gene: SLC9A3R1
Nephrocalcinosis or nephrolithiasis v1.50 TRPM6 Eleanor Williams changed review comment from: Comment on list classification: Demoting this gene from green to red. A PubMed search didn't find publications listing nephrocalicinosis/nephrolithiasis in association with this gene. Hypermagnesuria no hypomagnesemia is included on the eligibility statement for this disease.; to: Comment on list classification: Demoting this gene from green to red. A PubMed search didn't find publications listing nephrocalicinosis/nephrolithiasis in association with this gene. Hypermagnesuria not hypomagnesemia is included on the eligibility statement for this disease.
Nephrocalcinosis or nephrolithiasis v1.50 HNF4A Eleanor Williams Phenotypes for gene: HNF4A were changed from to Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, 616026
Nephrocalcinosis or nephrolithiasis v1.49 HNF4A Eleanor Williams Publications for gene: HNF4A were set to
Nephrocalcinosis or nephrolithiasis v1.48 SLC4A1 Eleanor Williams Phenotypes for gene: SLC4A1 were changed from distal renal tubular acidosis to distal renal tubular acidosis; Renal tubular acidosis, distal, AD, 179800; Renal tubular acidosis, distal, AR 611590
Nephrocalcinosis or nephrolithiasis v1.47 CLCNKB Eleanor Williams Added comment: Comment on mode of inheritance: In OMIM Autosomal recessive for Bartter syndrome, type 3 607364 and Digenic recessive for Bartter syndrome, type 4b, digenic 613090.
Nephrocalcinosis or nephrolithiasis v1.47 CLCNKB Eleanor Williams Mode of inheritance for gene: CLCNKB was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.46 CASR Eleanor Williams Added comment: Comment on mode of pathogenicity: Expert review states that Hypocalcemia can be caused by a mutation that inappropriately activates the receptor
Nephrocalcinosis or nephrolithiasis v1.46 CASR Eleanor Williams Mode of pathogenicity for gene: CASR was changed from to Other
Nephrocalcinosis or nephrolithiasis v1.45 BSND Eleanor Williams Added comment: Comment on mode of inheritance: AR in OMIM and Biallelic in Gene2Phenotype for Bartter syndrome, type 4a
Nephrocalcinosis or nephrolithiasis v1.45 BSND Eleanor Williams Mode of inheritance for gene: BSND was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.44 ATP6V1B1 Eleanor Williams Phenotypes for gene: ATP6V1B1 were changed from distal renal tubular acidosis to distal renal tubular acidosis; Renal tubular acidosis with deafness 267300
Nephrocalcinosis or nephrolithiasis v1.43 ATP6V0A4 Eleanor Williams commented on gene: ATP6V0A4
Nephrocalcinosis or nephrolithiasis v1.43 PHEX Eleanor Williams Classified gene: PHEX as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v1.43 PHEX Eleanor Williams Added comment: Comment on list classification: In light of expert review and consultation with the Genomics England clinical team it was decided to promote this gene from red to green. >3 cases reported with variants in this gene in patients with nephrocalicinosis.
Nephrocalcinosis or nephrolithiasis v1.43 PHEX Eleanor Williams Gene: phex has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.42 PHEX Eleanor Williams changed review comment from: Comment on mode of inheritance: Following XLD mode of inhertiance in OMIM, so changing to X-Linked: hemizyous mutation in males, monoallelic in females.; to: Comment on mode of inheritance: Following XLD mode of inhertiance in OMIM, so changing to X-Linked: hemizyous mutation in males, monoallelic in females. Monoallelic variants causing disease in females are reported e.g. PMID: 10439971 Filisetti et al 1999
Nephrocalcinosis or nephrolithiasis v1.42 PHEX Eleanor Williams Publications for gene: PHEX were set to
Nephrocalcinosis or nephrolithiasis v1.41 PHEX Eleanor Williams Phenotypes for gene: PHEX were changed from to Hypophosphatemic rickets, X-linked dominant 307800
Nephrocalcinosis or nephrolithiasis v1.40 FAM20A Eleanor Williams Classified gene: FAM20A as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v1.40 FAM20A Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. 3 independent cases where nephrocalcinosis is reported plus mouse knockout data showing a renal phenotype.
Nephrocalcinosis or nephrolithiasis v1.40 FAM20A Eleanor Williams Gene: fam20a has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.39 TRPM6 Eleanor Williams Classified gene: TRPM6 as Red List (low evidence)
Nephrocalcinosis or nephrolithiasis v1.39 TRPM6 Eleanor Williams Added comment: Comment on list classification: Demoting this gene from green to red. A PubMed search didn't find publications listing nephrocalicinosis/nephrolithiasis in association with this gene. Hypermagnesuria no hypomagnesemia is included on the eligibility statement for this disease.
Nephrocalcinosis or nephrolithiasis v1.39 TRPM6 Eleanor Williams Gene: trpm6 has been classified as Red List (Low Evidence).
Nephrocalcinosis or nephrolithiasis v1.38 PHEX Eleanor Williams Added comment: Comment on mode of inheritance: Following XLD mode of inhertiance in OMIM, so changing to X-Linked: hemizyous mutation in males, monoallelic in females.
Nephrocalcinosis or nephrolithiasis v1.38 PHEX Eleanor Williams Mode of inheritance for gene: PHEX was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Nephrocalcinosis or nephrolithiasis v1.37 SLC7A9 Eleanor Williams Phenotypes for gene: SLC7A9 were changed from Cystinuria to Cystinuria 220100
Nephrocalcinosis or nephrolithiasis v1.36 SLC3A1 Eleanor Williams Phenotypes for gene: SLC3A1 were changed from Cystinuria to Cystinuria 220100
Nephrocalcinosis or nephrolithiasis v1.35 SLC22A12 Eleanor Williams changed review comment from: Comment on mode of inheritance: The evidence for biallelic inheritance is stronger so setting to this for now.; to: Comment on mode of inheritance: The evidence for biallelic inheritance is stronger so setting to this for now. AR in OMIM.
Nephrocalcinosis or nephrolithiasis v1.35 CLCN5 Eleanor Williams changed review comment from: Comment on Mode of Inheritance - PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate. However, in OMIM the mode of inheritance for Hypophosphatemic rickets, Nephrolithiasis, type I and Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis) is XLR so keeping as Xlinked (biallelic in females) just now.; to: Comment on Mode of Inheritance - PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate. However, in OMIM the mode of inheritance for Dents disease, Hypophosphatemic rickets, Nephrolithiasis, type I and Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis is XLR so keeping as Xlinked (biallelic in females) just now.
Nephrocalcinosis or nephrolithiasis v1.35 SLC2A9 Eleanor Williams Phenotypes for gene: SLC2A9 were changed from to Hypouricemia, renal, 2, 612076
Nephrocalcinosis or nephrolithiasis v1.34 SLC2A9 Eleanor Williams Publications for gene: SLC2A9 were set to
Nephrocalcinosis or nephrolithiasis v1.33 SLC2A9 Eleanor Williams Classified gene: SLC2A9 as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v1.33 SLC2A9 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. 3 unrelated cases with Hypouricemia, renal, with Nephrolithiasis in some family members.
Nephrocalcinosis or nephrolithiasis v1.33 SLC2A9 Eleanor Williams Gene: slc2a9 has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.32 SLC2A9 Eleanor Williams Added comment: Comment on mode of inheritance: Both monoallelic and biallelic for Hypouricemia, renal. However, the reported cases with nephrolithiasis are homozygous.
Nephrocalcinosis or nephrolithiasis v1.32 SLC2A9 Eleanor Williams Mode of inheritance for gene: SLC2A9 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.31 SLC2A9 Eleanor Williams changed review comment from: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9)(R380W and R198C) in renal hypouricemic patients who have no URAT1 mutations but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.

PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case with renal hypouricemia and variant in SLC2A9 - no nephrolithiasis reported
PMID: 24940677 - 1 case with renal hypouricaemia and variant in SLC2A9 - no mention of nepthrolithiasis

Summary, clear association of variants in SLC2A9 with renal hypouricaemia . 3 cases reported with nepthrolithiasis/urothilthiasis but many more cases where it is not mentioned. ; to: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

Cases with nepthrolithiasis:
PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygous insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

Cases with no report of nepthrolithiasis:
PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9)(R380W and R198C) in renal hypouricemic patients who have no URAT1 mutations but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.

PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case with renal hypouricemia and variant in SLC2A9 - no nephrolithiasis reported
PMID: 24940677 - 1 case with renal hypouricaemia and variant in SLC2A9 - no mention of nepthrolithiasis

Summary, clear association of variants in SLC2A9 with renal hypouricaemia . 3 cases reported with nepthrolithiasis/urothilthiasis but many more cases where it is not mentioned.
Nephrocalcinosis or nephrolithiasis v1.31 SLC2A9 Eleanor Williams changed review comment from: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9)(R380W and R198C) in renal hypouricemic patients who have no URAT1 mutations but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.
PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case with renal hypouricemia and variant in SLC2A9 - no nephrolithiasis reported
PMID: 24940677 - 1 case with renal hypouricaemia and variant in SLC2A9 - no mention of nepthrolithiasis

Summary, clear association of variants in SLC2A9 with renal hypouricaemia . 3 cases reported with nepthrolithiasis/urothilthiasis but many more cases where it is not mentioned. ; to: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9)(R380W and R198C) in renal hypouricemic patients who have no URAT1 mutations but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.

PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case with renal hypouricemia and variant in SLC2A9 - no nephrolithiasis reported
PMID: 24940677 - 1 case with renal hypouricaemia and variant in SLC2A9 - no mention of nepthrolithiasis

Summary, clear association of variants in SLC2A9 with renal hypouricaemia . 3 cases reported with nepthrolithiasis/urothilthiasis but many more cases where it is not mentioned.
Nephrocalcinosis or nephrolithiasis v1.31 SLC22A12 Eleanor Williams Classified gene: SLC22A12 as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v1.31 SLC22A12 Eleanor Williams Added comment: Comment on list classification: Promoting from red to green. Sufficient number of cases with biallelic or compound heterozygous variants in this gene and a relevant phenotype reported. A few heterozygous cases also reported but the evidence is not so strong (asymptomatic family members with the same variant, only the SLC22A12 gene looked at).
Nephrocalcinosis or nephrolithiasis v1.31 SLC22A12 Eleanor Williams Gene: slc22a12 has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.30 SLC22A12 Eleanor Williams Phenotypes for gene: SLC22A12 were changed from to Hypouricemia, renal, 220150
Nephrocalcinosis or nephrolithiasis v1.29 SLC22A12 Eleanor Williams changed review comment from: Associated with Hypouricemia, renal #220150 (AR) in OMIM with Uric acid nephrolithiasis listed as a clinical feature.

PMID: 29486147 - Claverie-Martin et al 2018 - report patients from 6 unrelated Spanish families with Renal hypouricemia and variants in SLC22A12. Nephrolithiasis was reported in one Roma patient with compound heterozygous variants in this gene.

PMID: 29958533 - Vidanapathirana et al 2018 - report a 9 year old Sri Lankan boy with renal hypouricemia who presented with nephrolithiasis and haematuria. He was found to have a potentially deleterious missense variant c.1400C > T (p.T467 M, rs200104135) in heterozygous state. This variant has been previously identified in homozygous and/or compound heterozygous state with other causative SLC22A12 variant c.1245_1253del (p.L415_G417del) in Roma population. The genotype c.[1400C > T] was found in the proband, his sister and father (both asymptomatic).

PMID: 18492088 - Ichida et al 2008 - identified SLC22A12 mutations in 66 of 71 Japanese patients with hypouricemia. A total of 13 mutations, including 3 novel mutations, were identified. Urolithiasis occurred in 5 of the patients with variants in SLC22A12. 4 were homozygous or compound heterozygous, one was heterozygous. One variant G774A/W258X was the most common variant and is thought to be a founder mutation.

PMID: 15912381 - Cheong et al 2005 - studied the SLC22A12 gene in five Korean patients with idiopathic renal hypouricemia, 1 patient with a R90H substitution had uric acid urolithiasis. The variant was heterozygous.; to: Associated with Hypouricemia, renal #220150 (AR) in OMIM with Uric acid nephrolithiasis listed as a clinical feature.

PMID: 29486147 - Claverie-Martin et al 2018 - report patients from 6 unrelated Spanish families with Renal hypouricemia and variants in SLC22A12. Nephrolithiasis was reported in one Roma patient with compound heterozygous variants in this gene (L415_G417del, T467M).

PMID: 29958533 - Vidanapathirana et al 2018 - report a 9 year old Sri Lankan boy with renal hypouricemia who presented with nephrolithiasis and haematuria. He was found to have a potentially deleterious missense variant c.1400C > T (p.T467 M, rs200104135) in heterozygous state. This variant has been previously identified in homozygous and/or compound heterozygous state with other causative SLC22A12 variant c.1245_1253del (p.L415_G417del) in Roma population. The genotype c.[1400C > T] was found in the proband, his sister and father (both asymptomatic).

PMID: 18492088 - Ichida et al 2008 - identified SLC22A12 mutations in 66 of 71 Japanese patients with hypouricemia. A total of 13 mutations, including 3 novel mutations, were identified. Urolithiasis occurred in 5 of the patients with variants in SLC22A12. 4 were homozygous or compound heterozygous, one was heterozygous. One variant G774A/W258X was the most common variant and is thought to be a founder mutation.

PMID: 15912381 - Cheong et al 2005 - studied the SLC22A12 gene in five Korean patients with idiopathic renal hypouricemia, 1 patient with a R90H substitution had uric acid urolithiasis. The variant was heterozygous.
Nephrocalcinosis or nephrolithiasis v1.29 SLC22A12 Eleanor Williams Publications for gene: SLC22A12 were set to
Nephrocalcinosis or nephrolithiasis v1.28 SLC22A12 Eleanor Williams Added comment: Comment on mode of inheritance: The evidence for biallelic inheritance is stronger so setting to this for now.
Nephrocalcinosis or nephrolithiasis v1.28 SLC22A12 Eleanor Williams Mode of inheritance for gene: SLC22A12 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.27 PHEX Eleanor Williams commented on gene: PHEX: Personal communication from Detlef Bockenhauer. They see nephrocalcinosis in ~50% patients. It clearly is also related to treatment, but probably an intrinsic part of the disease.
Nephrocalcinosis or nephrolithiasis v1.27 HPRT1 Eleanor Williams Classified gene: HPRT1 as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v1.27 HPRT1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to green. > 3 unrelated cases with variants in this gene and Lesch-Nyhan syndrome with nephrocalcinosis as a feature are reported. Numerous variants are reported. Two publications.
Nephrocalcinosis or nephrolithiasis v1.27 HPRT1 Eleanor Williams Gene: hprt1 has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.26 HPRT1 Eleanor Williams Phenotypes for gene: HPRT1 were changed from to Lesch-Nyhan syndrome, 300322
Nephrocalcinosis or nephrolithiasis v1.25 HPRT1 Eleanor Williams Publications for gene: HPRT1 were set to
Nephrocalcinosis or nephrolithiasis v1.24 HNF4A Eleanor Williams Classified gene: HNF4A as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v1.24 HNF4A Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. Only one paper (PMID: 24285859) reporting variants in this gene associated with Fanconi syndrome and nephrocalcinosis and all patients have the same variant. Another paper reports that individuals with that variant have congenital hyperinsulinism and Fanconi syndrome but no nephrocalcinosis, however they are younger than the previously reported patients. Rating amber for now until another report confirms the association.
Nephrocalcinosis or nephrolithiasis v1.24 HNF4A Eleanor Williams Gene: hnf4a has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v1.23 FGF23 Eleanor Williams commented on gene: FGF23: Leaving this gene red as no published evidence to date to associate variants in this gene with Nephrocalcinosis or nephrolithiasis. However, it is a likely contender so added the watchlist tag.
Nephrocalcinosis or nephrolithiasis v1.23 FGF23 Eleanor Williams Tag watchlist tag was added to gene: FGF23.
Nephrocalcinosis or nephrolithiasis v1.23 STRADA Eleanor Williams commented on gene: STRADA: Despite red rating from reviewer, there is some published evidence that nephrocalcinosis is reported in patients with Polyhydramnios, so keeping green rating for now.
Nephrocalcinosis or nephrolithiasis v1.23 CLCN5 Eleanor Williams commented on gene: CLCN5
Nephrocalcinosis or nephrolithiasis v1.23 ZNF365 Detlef Bockenhauer reviewed gene: ZNF365: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 VDR Detlef Bockenhauer reviewed gene: VDR: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 TRPM6 Detlef Bockenhauer reviewed gene: TRPM6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 STRADA Detlef Bockenhauer reviewed gene: STRADA: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC9A3 Detlef Bockenhauer reviewed gene: SLC9A3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC6A20 Detlef Bockenhauer reviewed gene: SLC6A20: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC6A19 Detlef Bockenhauer reviewed gene: SLC6A19: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC36A2 Detlef Bockenhauer reviewed gene: SLC36A2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 GNA11 Detlef Bockenhauer reviewed gene: GNA11: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 CLCNKA Detlef Bockenhauer reviewed gene: CLCNKA: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 AP2S1 Detlef Bockenhauer reviewed gene: AP2S1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 AGK Detlef Bockenhauer reviewed gene: AGK: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 ADCY10 Detlef Bockenhauer reviewed gene: ADCY10: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 HNF4A Detlef Bockenhauer reviewed gene: HNF4A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC2A9 Detlef Bockenhauer reviewed gene: SLC2A9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC22A12 Detlef Bockenhauer reviewed gene: SLC22A12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.23 PHEX Detlef Bockenhauer reviewed gene: PHEX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 HPRT1 Detlef Bockenhauer reviewed gene: HPRT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 FGF23 Detlef Bockenhauer reviewed gene: FGF23: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 FAM20A Detlef Bockenhauer reviewed gene: FAM20A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.22 PHEX Eleanor Williams changed review comment from: Associated with Hypophosphatemic rickets, X-linked dominant (#307800)(XLD) in OMIM.

PMID: 31514490 - Şıklar et al 2019 - From 24 centers in Turkey, 166 patients with Hypophosphatemic rickets were included in the study data. Genetic analysis (n:75) showed PHEX mutation in 80% patients (60 patients). 27 patients developed nephrocalcinosis. However, higher treatment dose of phosphate and calcitriol has been detected in nephrocalcinosis group.

PMID: 29460029 - Chesher et al 2018 - clinical records of 59 adult patients from 35 kindreds with X-linked hypophosphatemia attending a single inherited metabolic disease service from 1998 were retrospectively reviewed. All had PHEX mutations (either directly obtained or inferred from the result of a first degree relative). 37 distinct variants were identified (14 not previously reported). Nephrocalcinosis was reported in 16/38 patients (42%) with at least one renal ultrasound performed. Treatment with vitamin D was associated with a small increase in urine calcium but there was no association between the presence or absence of nephrocalcinosis and whether or not the patient was currently being treated with vitamin D.

Will consult with Genomics England Clinical team with regards to nephrocalcinosis being associated with PHEX variants or a result of treatment for Hypophosphatemic rickets.; to: Associated with Hypophosphatemic rickets, X-linked dominant (#307800)(XLD) in OMIM.

PMID: 31514490 - Şıklar et al 2019 - Study of 166 patients with Hypophosphatemic rickets from 24 centers in Turkey. Genetic analysis (n:75) showed PHEX mutation in 80% patients (60 patients). 27 patients developed nephrocalcinosis. However, higher treatment dose of phosphate and calcitriol has been detected in nephrocalcinosis group.

PMID: 29460029 - Chesher et al 2018 - clinical records of 59 adult patients from 35 kindreds with X-linked hypophosphatemia attending a single inherited metabolic disease service from 1998 were retrospectively reviewed. All had PHEX mutations (either directly obtained or inferred from the result of a first degree relative). 37 distinct variants were identified (14 not previously reported). Nephrocalcinosis was reported in 16/38 patients (42%) with at least one renal ultrasound performed. Treatment with vitamin D was associated with a small increase in urine calcium but there was no association between the presence or absence of nephrocalcinosis and whether or not the patient was currently being treated with vitamin D.

Will consult with Genomics England Clinical team with regards to nephrocalcinosis being associated with PHEX variants or a result of treatment for Hypophosphatemic rickets.
Nephrocalcinosis or nephrolithiasis v1.22 HNF4A Eleanor Williams commented on gene: HNF4A
Nephrocalcinosis or nephrolithiasis v1.22 FGF23 Eleanor Williams commented on gene: FGF23
Nephrocalcinosis or nephrolithiasis v1.22 FGF23 Eleanor Williams gene: FGF23 was added
gene: FGF23 was added to Nephrocalcinosis or nephrolithiasis. Sources: Expert list
Mode of inheritance for gene: FGF23 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Nephrocalcinosis or nephrolithiasis v1.21 PHEX Eleanor Williams reviewed gene: PHEX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Nephrocalcinosis or nephrolithiasis v1.21 PHEX Eleanor Williams gene: PHEX was added
gene: PHEX was added to Nephrocalcinosis or nephrolithiasis. Sources: Expert list,Literature
Mode of inheritance for gene: PHEX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Nephrocalcinosis or nephrolithiasis v1.20 ZNF365 Eleanor Williams changed review comment from: Provisional association with {Nephrolithiasis, uric acid, susceptibility to} #605990 in OMIM.
PubMed search did not find any further papers beyond the association study of 2003 (PMID: 12740763)
Keep red rating.; to: Provisional association with {Nephrolithiasis, uric acid, susceptibility to} #605990 in OMIM.
PubMed search did not find any further papers beyond the study of 2003 (PMID: 12740763)
Keep red rating.
Nephrocalcinosis or nephrolithiasis v1.20 ZNF365 Eleanor Williams commented on gene: ZNF365
Nephrocalcinosis or nephrolithiasis v1.20 TRPM6 Eleanor Williams commented on gene: TRPM6
Nephrocalcinosis or nephrolithiasis v1.20 STRADA Eleanor Williams commented on gene: STRADA
Nephrocalcinosis or nephrolithiasis v1.20 SLC2A9 Eleanor Williams changed review comment from: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9) in renal hypouricemic patients who have no URAT1 mutations (R380W and R198C) but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.
PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case renal hypouricemia and with variant in SLC2A9 - no nephrolithiasis reported; to: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9)(R380W and R198C) in renal hypouricemic patients who have no URAT1 mutations but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.
PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case with renal hypouricemia and variant in SLC2A9 - no nephrolithiasis reported
PMID: 24940677 - 1 case with renal hypouricaemia and variant in SLC2A9 - no mention of nepthrolithiasis

Summary, clear association of variants in SLC2A9 with renal hypouricaemia . 3 cases reported with nepthrolithiasis/urothilthiasis but many more cases where it is not mentioned.
Nephrocalcinosis or nephrolithiasis v1.20 SLC2A9 Eleanor Williams commented on gene: SLC2A9
Nephrocalcinosis or nephrolithiasis v1.20 SLC22A12 Eleanor Williams edited their review of gene: SLC22A12: Changed publications: 29486147, 29958533, 18492088, 15912381; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.20 SLC22A12 Eleanor Williams commented on gene: SLC22A12
Nephrocalcinosis or nephrolithiasis v1.20 HPRT1 Eleanor Williams changed review comment from: Associated with HPRT-related gout #300323 (XLR) and Lesch-Nyhan syndrome #300322 (XLR) in OMIM, both of which have Nephrolithiasis listed as a clinical feature.

HPRT encodes the Hypoxanthine-guanine phosphoribosyltransferase enzyme. Partial deficiency can result in the overproduction of uric acid leading to a severe form of gout, whilst a virtual absence of HPRT activity causes the Lesch-Nyhan syndrome.

PMID: 31129767 - Cho et al 2019 - studied 26 Korean LNS patients from 23 unrelated families. Twenty one of the 23 LNS patients with available data (91.3%) showed renal manifestations such as hyperuricemia, nephrocalcinosis, or urinary stones. 16 patients from 13 families had nephrocalcinosis. Twenty different mutations in HPRT1 were identified from the 23 independent pedigrees.

PMID: 27079129 - Vargiami E et al 2016 - report of two cousins with Lesch-Nyhan syndrome and a confirmed novel HPRT gene mutation: c.65T>C, who both developed nephrocalcinosis and renal failure, findings not been previously published in children with HPRT deficiency.; to: Associated with HPRT-related gout #300323 (XLR) and Lesch-Nyhan syndrome #300322 (XLR) in OMIM, both of which have Nephrolithiasis listed as a clinical feature.

HPRT encodes the Hypoxanthine-guanine phosphoribosyltransferase enzyme. Partial deficiency can result in the overproduction of uric acid leading to a severe form of gout, whilst a virtual absence of HPRT activity causes Lesch-Nyhan syndrome.

PMID: 31129767 - Cho et al 2019 - studied 26 Korean LNS patients from 23 unrelated families. Twenty one of the 23 LNS patients with available data (91.3%) showed renal manifestations such as hyperuricemia, nephrocalcinosis, or urinary stones. 16 patients from 13 families had nephrocalcinosis. Twenty different mutations in HPRT1 were identified from the 23 independent pedigrees.

PMID: 27079129 - Vargiami E et al 2016 - report of two cousins with Lesch-Nyhan syndrome and a confirmed novel HPRT gene mutation: c.65T>C, who both developed nephrocalcinosis and renal failure, findings not been previously published in children with HPRT deficiency.
Nephrocalcinosis or nephrolithiasis v1.20 HPRT1 Eleanor Williams commented on gene: HPRT1
Nephrocalcinosis or nephrolithiasis v1.20 FAM20A Eleanor Williams Publications for gene: FAM20A were set to
Nephrocalcinosis or nephrolithiasis v1.19 FAM20A Eleanor Williams Phenotypes for gene: FAM20A were changed from to Amelogenesis imperfecta, type IG (enamel-renal syndrome) 204690
Nephrocalcinosis or nephrolithiasis v1.18 FAM20A Eleanor Williams changed review comment from: Associated with Amelogenesis imperfecta, type IG (enamel-renal syndrome) (#204690)(AR) in OMIM and AMELOGENESIS IMPERFECTA AND GINGIVAL FIBROMATOSIS SYNDROME (confirmed, biallelic) in Gene2Phenotype.

PMID: 23468644 - Wang et al 2013 - Characterized three families (from the Carribean, Jordan and Iran) with amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS) and identified, in each case, recessive FAM20A mutations with different variants in each family. Significantly, a kidney ultrasound of the family 2 proband revealed nephrocalcinosis, revising the diagnosis from AIGFS to Enamel-renal syndrome. Ultrasounds were not possible to obtain from families 1 and 3.

PMID: 30394349 - Dourado et al 2018 - investigated ERS characteristics in 11 patients from 5 Brazilian families.
All showed hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis. A biallelic loss of function variant in FAM20A [NG_029809.1: c.1447delG; p.(Glu483Lysfs*24)], was detected in all patients, strongly suggesting a founder effect.

PMID: 28298625 - Kantaputra et al 2017 (Abstract only accessed) - report three patients and their families with findings suggestive of Enamel-renal-gingival syndrome. Mutation analysis of FAM20A was performed in all patients and their family members. Patients with homozygous frameshift and compound heterozygous mutations in FAM20A had typical clinical findings along with periodontitis. The other had a novel homozygous missense mutation in exon 10, mild gingival fibromatosis and renal calcifications.

PMID: 22732358 - Vogel et al 2012 - two-thirds of Fam20a–/– mice had small kidneys with pitted surfaces, which showed widespread calcification (as well as a dental phenotype)

3 independent cases with nephrocalcinosis plus mouse knockout data. Not full penetrance for the renal phenotype.; to: Associated with Amelogenesis imperfecta, type IG (enamel-renal syndrome) (#204690)(AR) in OMIM and AMELOGENESIS IMPERFECTA AND GINGIVAL FIBROMATOSIS SYNDROME (confirmed, biallelic) in Gene2Phenotype.

PMID: 23468644 - Wang et al 2013 - Characterized three families (from the Caribbean, Jordan and Iran) with amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS) and identified, in each case, recessive FAM20A mutations with different variants in each family. Significantly, a kidney ultrasound of the family 2 proband revealed nephrocalcinosis, revising the diagnosis from AIGFS to Enamel-renal syndrome. Ultrasounds were not possible to obtain from families 1 and 3.

PMID: 30394349 - Dourado et al 2018 - investigated ERS characteristics in 11 patients from 5 Brazilian families.
All showed hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis. A biallelic loss of function variant in FAM20A [NG_029809.1: c.1447delG; p.(Glu483Lysfs*24)], was detected in all patients, strongly suggesting a founder effect.

PMID: 28298625 - Kantaputra et al 2017 (Abstract only accessed) - report three patients and their families with findings suggestive of Enamel-renal-gingival syndrome. Mutation analysis of FAM20A was performed in all patients and their family members. Patients with homozygous frameshift and compound heterozygous mutations in FAM20A had typical clinical findings along with periodontitis. The other had a novel homozygous missense mutation in exon 10, mild gingival fibromatosis and renal calcifications.

PMID: 22732358 - Vogel et al 2012 - two-thirds of Fam20a–/– mice had small kidneys with pitted surfaces, which showed widespread calcification (as well as a dental phenotype)

3 independent cases with nephrocalcinosis plus mouse knockout data. Not full penetrance for the renal phenotype.
Nephrocalcinosis or nephrolithiasis v1.18 FAM20A Eleanor Williams commented on gene: FAM20A
Nephrocalcinosis or nephrolithiasis v1.18 CLCNKA Eleanor Williams commented on gene: CLCNKA
Nephrocalcinosis or nephrolithiasis v1.18 ADCY10 Eleanor Williams commented on gene: ADCY10
Nephrocalcinosis or nephrolithiasis v1.18 Eleanor Williams List of related panels changed from Renal tract calcification (or Nephrolithiasis or nephrocalcinosis); Renal tract calcification (or Nephrolithiasis/nephrocalcinosis) to Renal tract calcification (or Nephrolithiasis or nephrocalcinosis); Renal tract calcification (or Nephrolithiasis/nephrocalcinosis); R256
Nephrocalcinosis or nephrolithiasis v1.17 BSND Eleanor Williams Phenotypes for gene: BSND were changed from Bartter Syndrome; Bartter syndrome, type 4a, 602522Sensorineural deafness with mild renal dysfunction, 602522 to Bartter Syndrome; Bartter syndrome, type 4a, 602522; Sensorineural deafness with mild renal dysfunction, 602522
Nephrocalcinosis or nephrolithiasis v1.15 Ellen McDonagh Panel name changed from Renal tract calcification (or Nephrolithiasis/nephrocalcinosis) to Nephrocalcinosis or nephrolithiasis
List of related panels changed from Renal tract calcification (or Nephrolithiasis or nephrocalcinosis) to Renal tract calcification (or Nephrolithiasis or nephrocalcinosis); Renal tract calcification (or Nephrolithiasis/nephrocalcinosis)
Panel types changed to Rare Disease 100K; GMS Rare Disease
Nephrocalcinosis or nephrolithiasis STRADA Louise Daugherty classified STRADA as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis STRADA Louise Daugherty Added gene to panel
Nephrocalcinosis or nephrolithiasis XDH Louise Daugherty reviewed XDH
Nephrocalcinosis or nephrolithiasis TRPM6 Ellen McDonagh commented on TRPM6
Nephrocalcinosis or nephrolithiasis TRPM6 Ellen McDonagh classified TRPM6 as green
Nephrocalcinosis or nephrolithiasis XDH Sarah Leigh classified XDH as green
Nephrocalcinosis or nephrolithiasis XDH Sarah Leigh commented on XDH
Nephrocalcinosis or nephrolithiasis TRPM6 Ellen McDonagh commented on TRPM6
Nephrocalcinosis or nephrolithiasis APRT Sarah Leigh classified APRT as green
Nephrocalcinosis or nephrolithiasis APRT Sarah Leigh commented on APRT