rs564069299
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000255.4(MMUT):c.1106G>A(p.Arg369His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,488 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. R369C) 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.1106G>A | p.Arg369His | missense_variant | 6/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.1106G>A | p.Arg369His | missense_variant | 6/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.1106G>A | p.Arg369His | missense_variant | 6/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152062Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000678 AC: 17AN: 250696Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135506
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461426Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727048
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152062Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74270
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 369 of the MUT protein (p.Arg369His). This variant is present in population databases (rs564069299, gnomAD 0.02%). This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 9929975, 16281286, 16490061, 17075691, 17113806, 22614770, 27167370, 27751223). 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: 203846). 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%. Experimental studies have shown that this missense change affects MUT function (PMID: 25125334). This variant disrupts the p.Arg369 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (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 | Mar 21, 2017 | The R369H missense change in the MUT gene has been reported previously in association with methylmalonic acidemia (Janata et al. 1997; Lempp et al. 2007; Han et al. 2015). Expression studies found that R369H is associated with 1.3% methylmalonyl-CoA mutase activity compared to wild type (Forny et al. 2014). The R369H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we interpret R369H to be a pathogenic variant. - |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 08, 2018 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 30, 2022 | - - |
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 | Mar 29, 2019 | Variant summary: MUT c.1106G>A (p.Arg369His) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha/beta 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 6.2e-05 in 276352 control chromosomes (gnomAD). The variant, c.1106G>A, has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Mikami_1999, Sakamoto_2007, Harrington_2016). These data indicate that the variant is very likely to be associated with disease. In vitro studies indicate that this variant is associated with 1.3% of MUT activity compared to WT (Forny_2014). Four 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 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at