Submissions for variant NM_000255.4(MMUT):c.278G>A (p.Arg93His)

gnomAD frequency: 0.00004  dbSNP: rs121918251

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724019	SCV000227077	pathogenic	not provided	2014-06-02	criteria provided, single submitter	clinical testing
Invitae	RCV000724019	SCV000812438	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 93 of the MUT protein (p.Arg93His). This variant is present in population databases (rs121918251, gnomAD 0.04%). This missense change has been observed in individuals with methylmalonic aciduria (PMID: 1670635, 16281286, 16490061). ClinVar contains an entry for this variant (Variation ID: 1880). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MUT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MUT function (PMID: 1670635, 7912889, 16281286). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780493	SCV000917794	pathogenic	Methylmalonic acidemia	2018-09-03	criteria provided, single submitter	clinical testing	Variant summary: MUT c.278G>A (p.Arg93His) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase catalytic alpha chain 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 6.1e-05 in 277218 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUT causing Methylmalonic Acidemia (6.1e-05 vs 0.0024), allowing no conclusion about variant significance. The variant, c.278G>A, has been reported in the literature in multiple homozygous individuals affected with Methylmalonic Acidemia (Imtiaz_2014). These data indicate that the variant is very likely to be associated with disease. The variant was reported in skin fibroblasts derived from a patient with neonatal methylmalonic aciduria, with no detectable methylmalonyl CoA mutase apoenzyme activity (Raff_1991). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000175568	SCV001519664	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2021-03-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000175568	SCV002810984	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2022-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000724019	SCV004021797	pathogenic	not provided	2023-01-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on propionate incorporation and protein function (Raff ML et al, 1991; Crane et al., 1994); 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: 33413471, 33726816, 1670635, 31523617, 31622506, 16281286, 7912889, 16490061)
Revvity Omics, Revvity	RCV000175568	SCV004238002	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2023-05-31	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000175568	SCV004805038	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2024-03-17	criteria provided, single submitter	research
OMIM	RCV000001957	SCV000022115	pathogenic	METHYLMALONIC ACIDURIA, mut(0) TYPE	1991-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000175568	SCV000258492	not provided	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		no assertion provided	literature only
Pathology and Clinical Laboratory Medicine, King Fahad Medical City	RCV000175568	SCV001438914	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		no assertion criteria provided	clinical testing