Submissions for variant NM_000255.4(MMUT):c.1867G>A (p.Gly623Arg)

gnomAD frequency: 0.00003  dbSNP: rs121918254

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427444	SCV000520995	pathogenic	not provided	2019-11-20	criteria provided, single submitter	clinical testing	Reported to be a common variant in individuals of African descent and functional analysis of G623R found that it is associated with significantly reduced enzyme activity compared to wild-type (Worgan et al., 2006; Janata et al., 1997).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 15643616, 7909321, 19375370, 17113806, 31525265, 25087612, 9285782, 8990001, 16281286)
Invitae	RCV000427444	SCV002148696	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 623 of the MUT protein (p.Gly623Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121918254, ExAC 0.01%). This missense change has been observed in individuals with methylmalonic aciduria (PMID: 7909321, 15643616, 16281286, 19375370). ClinVar contains an entry for this variant (Variation ID: 1884). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUT function (PMID: 7909321). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271364	SCV002555841	pathogenic	Methylmalonic acidemia	2022-06-13	criteria provided, single submitter	clinical testing	Variant summary: MUT c.1867G>A (p.Gly623Arg) results in a non-conservative amino acid change located in the Cobalamin (vitamin B12)-binding domain (IPR006158) of 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 8e-06 in 251316 control chromosomes. c.1867G>A has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia supported by characteristic biochemical findings (example, Acquaiva_2005, Worgan_2006, Brassier_2020). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000001961	SCV000022119	pathogenic	METHYLMALONIC ACIDURIA, mut(0) TYPE	1994-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000203390	SCV000258505	not provided	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		no assertion provided	literature only
Counsyl	RCV000203390	SCV001132252	likely pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-03-17	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001276633	SCV001463085	pathogenic	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	2020-09-16	no assertion criteria provided	clinical testing