Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000757497 | SCV000885746 | likely pathogenic | not specified | 2018-08-31 | criteria provided, single submitter | clinical testing | The MUT c.1889G>C; p.Gly630Ala variant, to our knowledge, is not described in the medical literature or gene-specific databases. It is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 630 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, another variant at this codon (c.1889G>A; p.Gly630Glu) has been reported in the homozygous and compound heterozygous state in individuals affected with methylmalonic academia (Crane 1994, Lempp 2006, Worgan 2006). Based on available information, this variant is considered likely pathogenic. Pathogenic MUT variants are inherited in an autosomal recessive manner and are associated with methylmalonic aciduria, mut(0) type (MIM: 251000). References: Crane AM et al. Clustering of mutations in methylmalonyl CoA mutase associated with mut- methylmalonic acidemia. Am J Hum Genet. 1994 Jul;55(1):42-50. Lempp TJ et al. Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations. Mol Genet Metab. 2007 Mar;90(3):284-90. Epub 2006 Nov 20. Worgan LC et al. Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat. 2006 Jan;27(1):31-43. |
| Labcorp Genetics |
RCV002533128 | SCV002960359 | pathogenic | not provided | 2022-09-13 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly630 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7912889, 17113806, 24865477, 27167370). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 618735). This missense change has been observed in individual(s) with clinical features of methylmalonic aciduria (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 630 of the MUT protein (p.Gly630Ala). |