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

gnomAD frequency: 0.00006  dbSNP: rs370596113

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000081739	SCV000329426	pathogenic	not provided	2023-12-12	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, 36184083)
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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000340205	SCV000934746	pathogenic	Cobalamin C disease	2025-01-06	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	2024-03-07	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
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000340205	SCV005417958	pathogenic	Cobalamin C disease		criteria provided, single submitter	clinical testing	PVS1_Strong+PM2_Supporting+PM3_VeryStrong+PP4
Natera, Inc.	RCV001273228	SCV001456020	pathogenic	Methylmalonic acidemia with homocystinuria cblC	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755764	SCV005362134	pathogenic	MMACHC-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The MMACHC c.481C>T variant is predicted to result in premature protein termination (p.Arg161*). This variant has been reported to be causative for methylmalonic aciduria and homocystinuria (Lerner-Ellis et al. 2006. PubMed ID: 16311595; Nogueira et al. 2008. PubMed ID: 18164228; Liu et al. 2010. PubMed ID: 20631720). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. Nonsense variants in MMACHC are expected to be pathogenic. This variant is interpreted as pathogenic.