ClinVar Miner

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

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Total submissions: 5
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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
GeneReviews RCV000175568 SCV000258492 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-01-07 no assertion criteria provided literature only
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.
Invitae RCV000175568 SCV000812438 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-12-05 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.
OMIM RCV000001957 SCV000022115 pathogenic METHYLMALONIC ACIDURIA, mut(0) TYPE 1991-01-01 no assertion criteria provided literature only

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