Submissions for variant NM_000255.4(MMUT):c.1125G>A (p.Met375Ile)

gnomAD frequency: 0.00156  dbSNP: rs148091558

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000271456	SCV000344853	uncertain significance	not provided	2016-08-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001082195	SCV000463870	uncertain significance	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000271456	SCV000641772	likely benign	not provided	2025-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000271456	SCV001822778	uncertain significance	not provided	2020-12-15	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign in association with methylmalonic acidemia to our knowledge; This variant is associated with the following publications: (PMID: 28337550)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001082195	SCV002048159	uncertain significance	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2022-03-17	criteria provided, single submitter	clinical testing	The MMUT c.1125G>A; p.Met375Ile variant (rs148091558) is reported in the literature in individuals affected with multiple sclerosis, but is also found in healthy controls (Traboulsee 2017). This variant is also reported in ClinVar (Variation ID: 290321), and is found in the general population with an overall allele frequency of 0.16% (438/282374 alleles) in the Genome Aggregation Database. The methionine at codon 375 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.853). Due to limited information, the clinical significance of the p.Met375Ile variant is uncertain at this time. References: Traboulsee AL et al. Common genetic etiology between "multiple sclerosis-like" single-gene disorders and familial multiple sclerosis. Hum Genet. 2017 Jun;136(6):705-714. PMID: 28337550.
Revvity Omics, Revvity	RCV001082195	SCV003808871	uncertain significance	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2022-06-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001276751	SCV001463279	uncertain significance	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	2019-12-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003940077	SCV004754655	likely benign	MMUT-related disorder	2022-05-22	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).