ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.323G>A (p.Arg108His) (rs483352778)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000502227 SCV000595871 pathogenic METHYLMALONIC ACIDURIA, mut(0) TYPE 2016-12-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781608 SCV000919780 pathogenic Methylmalonic acidemia 2017-11-10 criteria provided, single submitter clinical testing Variant summary: The MUT c.323G>A (p.Arg108His) variant involves the alteration of a conserved nucleotide located at the SB, substrate binding (beta alpha) 8 barrel domain (Lempp_2007). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 6/246336 control chromosomes at a frequency of 0.0000244, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUT variant (0.0024152). This variant has been reported in multiple affected individuals mostly as compound heterozygotes and the patients' fibroblasts presented with a marked decrease in MCM enzyme activity (Acquaviva_2001 and Lempp_2007). Variants involving codon R108 (p.R108C, p.R108G, and p.R108H) have been reported in multiple patients with Methylmalonic aciduria suggesting it is a mutation hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000664555 SCV000954894 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 108 of the MUT protein (p.Arg108His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs483352778, ExAC 0.006%). This variant has been observed in combination with another MUT variants in several individuals affected with methylmalonic aciduria (PMID: 11528502, 16281286, 17113806). ClinVar contains an entry for this variant (Variation ID: 100707). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg108 amino acid residue in MUT. Other variants that disrupt this residue have been observed in affected individuals (PMID: 16281286, 17075691, 24059531, 23045948, 2661559, 22614770, 24464670, 27578510), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Medical Genetics Unit, Ain Shams University Pediatrics Hospital RCV000162231 SCV000119930 not provided not provided no assertion provided not provided
Counsyl RCV000664555 SCV000788539 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-10-03 no assertion criteria provided clinical testing

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