Nephrocalcinosis or nephrolithiasis
Gene: SLC9A3R1In 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.Created: 13 Nov 2019, 4:42 p.m. | Last Modified: 13 Nov 2019, 4:58 p.m.
Panel Version: 1.50
Added new-gene-name tag, new approved HGNC gene symbol for SLC9A3R1 (HGNC:11075) is NHERF1.Created: 8 Feb 2023, 1:52 p.m. | Last Modified: 8 Feb 2023, 1:52 p.m.
Panel Version: 3.4
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.Created: 14 Nov 2019, 9:20 a.m. | Last Modified: 14 Nov 2019, 9:20 a.m.
Panel Version: 1.51
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).Created: 13 Nov 2019, 11:04 a.m. | Last Modified: 13 Nov 2019, 11:13 a.m.
Panel Version: 1.50
Comment on mode of inheritance: Confirmed by OMIM.Created: 20 May 2016, 10:08 a.m.
Comment on list classification: Promoted from red to green due to expert review, and more than 3 unrelated cases reported in OMIM.Created: 20 May 2016, 10:08 a.m.
Mode of inheritance provided by Expert list was "AD".Created: 8 Jul 2015, 12:48 p.m.
Tag new-gene-name tag was added to gene: SLC9A3R1.
Gene: slc9a3r1 has been classified as Amber List (Moderate Evidence).
This gene has been classified as Green List (High Evidence).
Mode of inheritance for SLC9A3R1 was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for SLC9A3R1 were set to
This gene has been classified as Green List (High Evidence).
SLC9A3R1 was added to Renal tract calcification (or Nephrolithiasis/nephrocalcinosis)panel. Sources: Expert
SLC9A3R1 was added to Renal tract calcification (or Nephrolithiasis/nephrocalcinosis)panel. Sources: Radboud University Medical Center, Nijmegen