Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genetic Services Laboratory, |
RCV000001964 | SCV000595872 | pathogenic | METHYLMALONIC ACIDURIA, mut(0) TYPE | 2016-04-06 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV001376644 | SCV000641779 | pathogenic | not provided | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 108 of the MUT protein (p.Arg108Cys). This variant is present in population databases (rs121918257, gnomAD 0.08%). This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 2661559, 16281286, 17075691, 22614770, 23045948, 24059531, 24464670, 27578510). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1887). 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%. This variant disrupts the p.Arg108 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16281286, 17113806, 22614770, 23430940, 25750861). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001192656 | SCV001360915 | pathogenic | Methylmalonic acidemia | 2019-01-14 | criteria provided, single submitter | clinical testing | Variant summary: MUT c.322C>T (p.Arg108Cys) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha chain, catalytic domain 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 0.00011 in 246146 control chromosomes. c.322C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Worgan_2006, Harrington_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity as measured by decreased incorporation of label from carbon-14 labeled propionate into cellular macromolecules (Worgan_2006). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Gene |
RCV001376644 | SCV001804136 | pathogenic | not provided | 2021-03-09 | criteria provided, single submitter | clinical testing | 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: 16281286, 30564975, 24464670, 31622506, 31998365, 31525265, 31466887, 27578510, 29330964, 26454439) |
Fulgent Genetics, |
RCV000203340 | SCV002778542 | pathogenic | Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency | 2022-02-18 | criteria provided, single submitter | clinical testing | |
Rady Children's Institute for Genomic Medicine, |
RCV001192656 | SCV004046422 | pathogenic | Methylmalonic acidemia | criteria provided, single submitter | clinical testing | This variant has been previously reported as a compound heterozygous and homozygous change in patients with methylmalonic acidemia (PMID: 16281286, 17075691, 24059531, 23045948, 2661559, 22614770, 24464670, 27578510). The c.322C>T (p.Arg108Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.012% (30/251326), and is absent in the homozygous state; thus it is presumed to be rare. The c.322C>T (p.Arg108Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.322C>T (p.Arg108Cys) variant is classified as a Pathogenic. | |
Ambry Genetics | RCV004018538 | SCV004969113 | pathogenic | not specified | 2021-08-18 | criteria provided, single submitter | clinical testing | The c.322C>T (p.R108C) alteration is located in exon 2 (coding exon 1) of the MUT gene. This alteration results from a C to T substitution at nucleotide position 322, causing the arginine (R) at amino acid position 108 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (30/251326) total alleles studied. The highest observed frequency was 0.08% (29/34552) of Latino alleles. This mutation has been reported in the homozygous and compound heterozygous state in several individuals with MUT-related methylmalonic aciduria (Worgan, 2006; Zhang, 2019; Han, 2020). Another alteration at the same codon, p.R108H (c.323G>A), has been detected in individuals with MUT-related methylmalonic aciduria in conjunction with a second MUT alteration (Worgan, 2006; Lempp, 2007). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
OMIM | RCV000001964 | SCV000022122 | pathogenic | METHYLMALONIC ACIDURIA, mut(0) TYPE | 2006-01-01 | no assertion criteria provided | literature only | |
Gene |
RCV000203340 | SCV000258495 | not provided | Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency | no assertion provided | literature only | mut(0) enzymatic subtype when homozygous | |
Natera, |
RCV001271723 | SCV001453071 | pathogenic | Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency | 2020-09-16 | no assertion criteria provided | clinical testing | |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV001376644 | SCV001954835 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV001376644 | SCV001966145 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Prevention |
RCV004752677 | SCV005363066 | pathogenic | MMUT-related disorder | 2024-04-03 | no assertion criteria provided | clinical testing | The MMUT c.322C>T variant is predicted to result in the amino acid substitution p.Arg108Cys. This variant has been documented as a recurrent variant causative for methylmalonic acidemia, in both the homozygous and compound heterozygous state (e.g., Worgan et al. 2006. PubMed ID: 16281286; Park et al. 2016. PubMed ID: 27578510; Zhang et al. 2019. PubMed ID: 31998365; Brassier et al. 2020. PubMed ID: 31525265; Han et al. 2020. PubMed ID: 31466887). In the homozygous state, it has been reported as a mut0 variant; it is particularly common in individuals of Hispanic descent (Worgan et al. 2006. PubMed ID: 16281286). Based on these observations and the data in the above table, we classify this variant as pathogenic. |