rs121918257
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000255.4(MMUT):c.322C>T(p.Arg108Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108H) has been classified as Pathogenic.
Frequency
Consequence
NM_000255.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.322C>T | p.Arg108Cys | missense_variant | 2/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.322C>T | p.Arg108Cys | missense_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.322C>T | p.Arg108Cys | missense_variant | 2/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152094Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000119 AC: 30AN: 251326Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135840
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461840Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727226
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74414
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2021 | 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) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | 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. - |
Methylmalonic acidemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 14, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | 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. - |
METHYLMALONIC ACIDURIA, mut(0) TYPE Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 06, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2006 | - - |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | mut(0) enzymatic subtype when homozygous - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 18, 2022 | - - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 18, 2021 | 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. - |
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at