Submissions for variant NM_015506.3(MMACHC):c.332G>A (p.Arg111Gln)

gnomAD frequency: 0.00123  dbSNP: rs200300254

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000955713	SCV001102433	likely benign	Cobalamin C disease	2024-01-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509584	SCV002819588	uncertain significance	not specified	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.332G>A (p.Arg111Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 249418 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MMACHC causing Methylmalonic Acidemia With Homocystinuria (0.0003 vs 0.0032), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.332G>A in individuals affected with Methylmalonic Acidemia With Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV003127556	SCV003803459	uncertain significance	not provided	2023-02-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32579932)
Revvity Omics, Revvity	RCV000955713	SCV003808850	uncertain significance	Cobalamin C disease	2019-01-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000955713	SCV003835442	uncertain significance	Cobalamin C disease	2022-10-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV003127556	SCV005260350	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV001277242	SCV001464149	likely benign	Methylmalonic acidemia with homocystinuria cblC	2020-04-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003943077	SCV004759094	likely benign	MMACHC-related disorder	2022-07-15	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).