ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.389A>G (p.Tyr130Cys)

gnomAD frequency: 0.00014  dbSNP: rs200094982
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV000260401 SCV000357924 uncertain significance Disorders of Intracellular Cobalamin Metabolism 2017-04-27 criteria provided, single submitter clinical testing The MMACHC c.389A>G (p.Tyr130Cys) missense variant has been reported in at least two studies in which it is found in a compound heterozygous state in a total of three individuals with disorders of intracellular cobalamin metabolism (Lerner-Ellis et al. 2009; Cornec-Le Gall et al. 2014). The p.Tyr130Cys variant was absent from 52 controls and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Tyr130Cys variant is therefore classified as a variant of unknown significance, but suspicious for pathogenicity for disorders of intracellular cobalamin metabolism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genetic Services Laboratory,University of Chicago RCV000504286 SCV000595813 likely pathogenic Cobalamin C disease 2016-07-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV000504286 SCV001162904 pathogenic Cobalamin C disease criteria provided, single submitter clinical testing
Invitae RCV000504286 SCV001235685 pathogenic Cobalamin C disease 2021-11-24 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 130 of the MMACHC protein (p.Tyr130Cys). This variant is present in population databases (rs200094982, gnomAD 0.02%). This missense change has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 19370762, 24210589; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 297484). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MMACHC protein function. This variant disrupts the p.Tyr130 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been observed in individuals with MMACHC-related conditions (PMID: 16311595, 19370762), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074563 SCV001240154 likely pathogenic Retinal dystrophy 2018-12-18 criteria provided, single submitter clinical testing
GeneDx RCV001582921 SCV001819866 likely pathogenic not provided 2020-12-02 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32481360, 32071835, 25398587, 30178268, 30197982, 19370762, 24210589)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000504286 SCV002500645 pathogenic Cobalamin C disease 2022-03-25 criteria provided, single submitter clinical testing Variant summary: MMACHC c.389A>G (p.Tyr130Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249408 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in MMACHC causing Methylmalonic Acidemia with Homocystinuria (0.0032), allowing no conclusion about variant significance. The variant, c.389A>G, has been reported in the literature in several compound heterozygous individuals affected with Methylmalonic Acidemia with Homocystinuria (e.g. Lerner-Ellis_2009, Cornec-LeGall_2014, Higashimoto_2020, Bourque_2021), including a family with three affected individuals (Higashimoto_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=1), likely pathogenic (n=4) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories,Mayo Clinic RCV001582921 SCV002520017 likely pathogenic not provided 2021-12-20 criteria provided, single submitter clinical testing PP3, PM2, PM3_strong
PerkinElmer Genomics RCV000504286 SCV002023489 likely pathogenic Cobalamin C disease 2021-06-24 no assertion criteria provided clinical testing

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