Submissions for variant NM_000255.4(MMUT):c.278G>A (p.Arg93His) (rs121918251)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000724019	SCV000227077	pathogenic	not provided	2014-06-02	criteria provided, single submitter	clinical testing
Invitae	RCV000175568	SCV000812438	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2019-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 93 of the MUT protein (p.Arg93His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121918251, ExAC 0.05%). This variant has been reported to be homozygous or compound heterozygous in several individuals affected with methylmalonic aciduria (PMID: 1670635, 16281286, 16490061). ClinVar contains an entry for this variant (Variation ID: 1880). Experimental studies have shown that this missense change results in very low or undetectable levels of methylmalonyl-CoA mutase activity (PMID: 1670635, 16281286, 7912889). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America	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.
OMIM	RCV000001957	SCV000022115	pathogenic	METHYLMALONIC ACIDURIA, mut(0) TYPE	1991-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000175568	SCV000258492	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2016-01-07	no assertion criteria provided	literature only