ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.481C>T (p.Arg161Ter)

gnomAD frequency: 0.00006  dbSNP: rs370596113
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000081739 SCV000329426 pathogenic not provided 2023-01-11 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation, as the last 122 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27289364, 19370762, 18164228, 28071971, 28693988, 20696242, 16311595, 20631720, 19760748, 17853453, 16714133, 33691766, 30157807, 31137025, 31503356, 32778825, 34215320, 32005694, 35361390)
Eurofins Ntd Llc (ga) RCV000081739 SCV000331416 pathogenic not provided 2013-06-06 criteria provided, single submitter clinical testing
Counsyl RCV000340205 SCV000486526 pathogenic Cobalamin C disease 2016-11-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000340205 SCV000919671 pathogenic Cobalamin C disease 2018-01-08 criteria provided, single submitter clinical testing Variant summary: The MMACHC c.481C>T (p.Arg161X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.609G>A, p.Trp203X; c.615C>G, p.Tyr205X; c.666C>A, p.Tyr222X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 6/276988 control chromosomes (gnomAD) at a frequency of 0.0000217, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000340205 SCV000934746 pathogenic Cobalamin C disease 2024-01-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg161*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 122 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs370596113, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 16311595, 20631720). ClinVar contains an entry for this variant (Variation ID: 95703). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the MMACHC protein in which other variant(s) (p.Val183Thrfs*5) have been determined to be pathogenic (PMID: 16311595, 19370762, 23954310). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000340205 SCV001162913 pathogenic Cobalamin C disease criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000340205 SCV001752449 pathogenic Cobalamin C disease 2021-06-30 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000340205 SCV003807763 pathogenic Cobalamin C disease 2022-08-05 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1 strong, PS4 strong, PM2 supporting, PM3 very strong
Genome-Nilou Lab RCV000340205 SCV004178186 pathogenic Cobalamin C disease 2023-04-11 criteria provided, single submitter clinical testing
Natera, Inc. RCV001273228 SCV001456020 pathogenic Methylmalonic acidemia with homocystinuria cblC 2020-09-16 no assertion criteria provided clinical testing

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