rs1446389693
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000255.4(MMUT):c.654A>C(p.Gln218His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,404 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q218E) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.654A>C | p.Gln218His | missense_variant | 3/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.654A>C | p.Gln218His | missense_variant | 3/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.654A>C | p.Gln218His | missense_variant | 3/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251050Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135708
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461198Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 726922
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 218 of the MUT protein (p.Gln218His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 10923046, 16281286). This variant is also known as 730A>C. ClinVar contains an entry for this variant (Variation ID: 551243). 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). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2021 | - - |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 01, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 30, 2017 | - - |
MMUT-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 13, 2023 | The MMUT c.654A>C variant is predicted to result in the amino acid substitution p.Gln218His. This variant has been reported in the homozygous state or heterozygous state with a second pathogenic MMUT variant in individuals with methylmalonic acidemia (Fuchshuber et al. 2000. PubMed ID: 10923046; Worgan et al. 2006. PubMed ID: 16281286; Hörster et al. 2020. PubMed ID: 32754920). The p.Gln218 amino acid is located within the enzyme substrate binding channel, and in experimental studies the p.Gln218His substitution lead to severely reduced enzyme activity (Forny et al. 2014. PubMed ID: 25125334). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-49425503-T-G). Taken together, this variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at