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Mitochondrial disorders v10.23 HSPA9 Ida Ertmanska edited their review of gene: HSPA9: Added comment: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (pC487Sfs*3 & p.E577K in Family K; p.V296* & ?p.203_204ins3 in family L).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population.
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.
FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR).

PMID: 30401706 Ducamp & Fleming, 2018 review
"a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant"

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; Changed publications to: 25550197, 26491070, 30401706, 33398880, 36094340, 38360212; Changed phenotypes to: Anemia, sideroblastic, 4, OMIM:182170, sideroblastic anemia, MONDO:0015194, Even-plus syndrome, OMIM:616854, even-plus syndrome, MONDO:0014801; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mitochondrial disorders v9.32 PPOX Ida Ertmanska edited their review of gene: PPOX: Added comment: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should remain Green for Mitochondrial disorders.; Changed phenotypes to: Variegate porpComment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408, 9811936, 2004012, 35164799, 37879139, 40114189). PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025. Based on the available evidence, this gene should remain Green for Variegate porphyria.hyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577
Mitochondrial disorders v4.167 G6PC Arina Puzriakova Phenotypes for gene: G6PC were changed from Glycogen storage disease Ia to Glycogen storage disease Ia, OMIM:232200
Mitochondrial disorders v4.125 PCK2 Achchuthan Shanmugasundram Classified gene: PCK2 as Amber List (moderate evidence)
Mitochondrial disorders v4.125 PCK2 Achchuthan Shanmugasundram Gene: pck2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.124 PCK2 Achchuthan Shanmugasundram Phenotypes for gene: PCK2 were changed from PEPCK deficiency, mitochondrial, OMIM:261650; Abnormal gait; peripheral neuropathy to PEPCK deficiency, mitochondrial, OMIM:261650; Abnormal gait; peripheral neuropathy
Mitochondrial disorders v4.124 PCK2 Achchuthan Shanmugasundram Phenotypes for gene: PCK2 were changed from Abnormal gait; peripheral neuropathy to PEPCK deficiency, mitochondrial, OMIM:261650; Abnormal gait; peripheral neuropathy
Mitochondrial disorders v4.123 PCK2 Achchuthan Shanmugasundram reviewed gene: PCK2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36845668; Phenotypes: PEPCK deficiency, mitochondrial, OMIM:261650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.113 PCK2 Hannah Knight gene: PCK2 was added
gene: PCK2 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: PCK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCK2 were set to 36845668
Phenotypes for gene: PCK2 were set to Abnormal gait; peripheral neuropathy
Review for gene: PCK2 was set to AMBER
Added comment: PMID: 36845668 (2023) identified three patients in two families with a common phenotype and likely pathogenic variants in PCK2:
A 3-year-old girl with ataxia and weakness, who was found to be compound heterozygous for p.Ser23Ter and p.Pro170Leu
Two siblings with abnormal gait and weakness who were found to both be homozygous for p.Arg193Ter. Unaffected sibling did not carry the variant
Sources: Literature
Mitochondrial disorders v4.23 PC Arina Puzriakova Phenotypes for gene: PC were changed from Pyruvate carboxylase deficiency to Pyruvate carboxylase deficiency, OMIM:266150
Mitochondrial disorders v4.13 MPC1 Arina Puzriakova Phenotypes for gene: MPC1 were changed from Mitochondrial pyruvate carrier deficiency, 614741 to Mitochondrial pyruvate carrier deficiency, OMIM:614741
Mitochondrial disorders v2.109 G6PC Arina Puzriakova commented on gene: G6PC
Mitochondrial disorders v2.108 G6PC Arina Puzriakova Source Expert Review Red was added to G6PC.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.84 XPNPEP3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least three variants reported in three unrelated cases (PMID: 32660933; 20179356). Two of the variants were terminating (RCV000000069, RCV001554332) and the third variant was a missense variant (RCV000000068), that seems to activate a cryptic splice site; RT-PCR of lymphoblastoid cells showed that this resulted in the inclusion of intronic bases and a frameshift. Cilia-related function was examined by the suppression of zebrafish xpnpep3, resulting in phenotypes reminiscent of ciliopathy morphants, this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal (PMID: 20179356).; to: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least three variants were reported in three unrelated cases (PMID: 32660933; 20179356). Two of the variants were terminating (RCV000000069, RCV001554332) and the third was a missense variant (RCV000000068), that seems to activate a cryptic splice site; RT-PCR of lymphoblastoid cells showed that this resulted in the inclusion of intronic bases and a frameshift. Cilia-related function was examined by the suppression of zebrafish xpnpep3, resulting in phenotypes reminiscent of ciliopathy morphants, this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal (PMID: 20179356).
Mitochondrial disorders v2.84 XPNPEP3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least three variants reported in three unrelated cases (PMID: 32660933; 20179356). Two of the variants were terminating (RCV000000069, RCV001554332) and the third variant was a missense variant (RCV000000068), that seems to activate a cryptic splice site; RT-PCR of lymphoblastoid cells showed that this resulted in the inclusion of intronic bases and a frameshift.; to: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least three variants reported in three unrelated cases (PMID: 32660933; 20179356). Two of the variants were terminating (RCV000000069, RCV001554332) and the third variant was a missense variant (RCV000000068), that seems to activate a cryptic splice site; RT-PCR of lymphoblastoid cells showed that this resulted in the inclusion of intronic bases and a frameshift. Cilia-related function was examined by the suppression of zebrafish xpnpep3, resulting in phenotypes reminiscent of ciliopathy morphants, this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal (PMID: 20179356).
Mitochondrial disorders v2.84 XPNPEP3 Sarah Leigh edited their review of gene: XPNPEP3: Added comment: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least three variants reported in three unrelated cases (PMID: 32660933; 20179356). Two of the variants were terminating (RCV000000069, RCV001554332) and the third variant was a missense variant (RCV000000068), that seems to activate a cryptic splice site; RT-PCR of lymphoblastoid cells showed that this resulted in the inclusion of intronic bases and a frameshift.; Changed rating: AMBER
Mitochondrial disorders v2.35 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Mitochondrial disorders v2.19 G6PC Catherine Snow Tag new-gene-name tag was added to gene: G6PC.
Mitochondrial disorders v2.19 G6PC Catherine Snow commented on gene: G6PC
Mitochondrial disorders v2.5 G6PC Zornitza Stark reviewed gene: G6PC: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Glycogen storage disease Ia, MIM# 232200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v1.349 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from to Multiple mitochondrial dysfunctions syndrome 6, 617954
Mitochondrial disorders v1.348 PMPCB Sarah Leigh Publications for gene: PMPCB were set to
Mitochondrial disorders v1.347 PMPCB Sarah Leigh Mode of inheritance for gene: PMPCB was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v1.346 PMPCB Sarah Leigh Classified gene: PMPCB as Green List (high evidence)
Mitochondrial disorders v1.346 PMPCB Sarah Leigh Gene: pmpcb has been classified as Green List (High Evidence).
Mitochondrial disorders v1.293 PMPCB Sarah Leigh gene: PMPCB was added
gene: PMPCB was added to Mitochondrial disorders. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PMPCB was set to
Mitochondrial disorders v1.254 MPC1 Ivone Leong Classified gene: MPC1 as Green List (high evidence)
Mitochondrial disorders v1.254 MPC1 Ivone Leong Gene: mpc1 has been classified as Green List (High Evidence).
Mitochondrial disorders v1.253 MPC1 Ivone Leong Added comment: Comment on publications: PMID: 27176894 and 27835892 describe mouse models of MPC1 (a knockin model and a knockout model) showing the effects MPC1 has on mitochondrial function.
Mitochondrial disorders v1.253 MPC1 Ivone Leong Publications for gene: MPC1 were set to 22628558
Mitochondrial disorders v1.252 MPC1 Ivone Leong Publications for gene: MPC1 were set to
Mitochondrial disorders v1.251 MPC1 Ivone Leong Mode of inheritance for gene: MPC1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders MPC1 Zornitza Stark reviewed gene: MPC1