rs121918251
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000255.4(MMUT):c.278G>A(p.Arg93His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,614,118 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. R93C) has been classified as Likely 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.278G>A | p.Arg93His | missense_variant | 2/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.278G>A | p.Arg93His | missense_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.278G>A | p.Arg93His | missense_variant | 2/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251462Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135906
GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727246
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74428
ClinVar
Submissions by phenotype
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Mar 12, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 02, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 31, 2023 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 93 of the MUT protein (p.Arg93His). This variant is present in population databases (rs121918251, gnomAD 0.04%). This missense change has been observed in individuals with methylmalonic aciduria (PMID: 1670635, 16281286, 16490061). ClinVar contains an entry for this variant (Variation ID: 1880). 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: 1670635, 7912889, 16281286). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 02, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2023 | Published functional studies demonstrate a damaging effect on propionate incorporation and protein function (Raff ML et al, 1991; Crane et al., 1994); 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: 33413471, 33726816, 1670635, 31523617, 31622506, 16281286, 7912889, 16490061) - |
Methylmalonic acidemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 03, 2018 | Variant summary: MUT c.278G>A (p.Arg93His) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase catalytic alpha chain 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 6.1e-05 in 277218 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUT causing Methylmalonic Acidemia (6.1e-05 vs 0.0024), allowing no conclusion about variant significance. The variant, c.278G>A, has been reported in the literature in multiple homozygous individuals affected with Methylmalonic Acidemia (Imtiaz_2014). These data indicate that the variant is very likely to be associated with disease. The variant was reported in skin fibroblasts derived from a patient with neonatal methylmalonic aciduria, with no detectable methylmalonyl CoA mutase apoenzyme activity (Raff_1991). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
METHYLMALONIC ACIDURIA, mut(0) TYPE Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1991 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at