rs772552898
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000255.4(MMUT):c.1105C>T(p.Arg369Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R369H) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.1105C>T | p.Arg369Cys | missense_variant | 6/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.1105C>T | p.Arg369Cys | missense_variant | 6/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.1105C>T | p.Arg369Cys | missense_variant | 6/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152024Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250668Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135498
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461472Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 727048
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152024Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74260
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 09, 2020 | The MMUT c.1105C>T; p.Arg369Cys variant (rs772552898) is reported in the literature in the compound heterozygous state with other pathogenic variants in multiple individuals affected with methylmalonic aciduria (Han 2015, Jung 2005, Nizon 2013, Sakamoto 2007, Worgan 2006). This variant is reported in ClinVar (Variation ID: 218989), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 369 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.1106G>A; p.Arg369His) has been reported in individuals with methylmalonic aciduria and is considered pathogenic (Han 2015, Jung 2005, Sakamoto 2007, Worgan 2006). Based on available information, the p.Arg369Cys variant is considered to be pathogenic. References: Han LS et al. Clinical features and MUT gene mutation spectrum in Chinese patients with isolated methylmalonic acidemia: identification of ten novel allelic variants. World J Pediatr. 2015 Nov;11(4):358-65. Jung JW et al. Mutation analysis of the MCM gene in Korean patients with MMA. Mol Genet Metab. 2005 Apr;84(4):367-70. Epub 2004 Dec 19. Nizon M et al. Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. Orphanet J Rare Dis. 2013 Sep 23;8:148. Sakamoto O et al. Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia. J Hum Genet. 2007;52(1):48-55. 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 369 of the MUT protein (p.Arg369Cys). This variant is present in population databases (rs772552898, gnomAD 0.006%). This missense change has been observed in individuals with methylmalonic acidemia (PMID: 15781199, 16281286, 17075691). ClinVar contains an entry for this variant (Variation ID: 218989). 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.Arg369 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16281286, 25125334, 27751223; Invitae). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2016 | The R369C missense variant in the MUT gene has been reported previously in multiple patients in association with methylmalonic acidemia (MMA) due to methylmalonyl-CoA mutase deficiency (Jung et al. 2005; Ktena et al. 2015; Sakamoto et al. 2007; Merinero et al. 2008; Nizon et al. 2013). R369C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts R369C is probably damaging to the protein structure/function. Furthermore, a conservative amino acid substitution at the same position (R369H) appears to be a common variant in Japanese patients with MMA and is reported to be associated with 1% of wild-type enzyme activity (Sakamoto et al. 2007). Therefore, we interpret R369C to be a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2022 | - - |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 20, 2017 | - - |
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Methylmalonic acidemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 30, 2021 | Variant summary: MMUT (legacy gene name MUT) c.1105C>T (p.Arg369Cys) 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 2e-05 in 250668 control chromosomes. c.1105C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (example, Forny_2016, Jung_2004, Worgan_2006). 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 propionate incorporation and Methylmalonyl-CoA mutase enzyme activity values that were considerably lower than controls (example, Forny_2016, Worgan_2006). Multiple clinical diagnostic laboratories and the Gene Reviews database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at