rs1085307929
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000255.4(MMUT):c.917C>T(p.Ser306Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S306Y) 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 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.917C>T | p.Ser306Phe | missense_variant | 5/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.917C>T | p.Ser306Phe | missense_variant | 5/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.917C>T | p.Ser306Phe | missense_variant | 5/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1AN: 1459082Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726008
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 553978). This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 16281286; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 306 of the MUT protein (p.Ser306Phe). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 29, 2024 | Variant summary: MMUT c.917C>T (p.Ser306Phe) results in a non-conservative amino acid change located in the methylmalonyl-CoA mutase, alpha chain, catalytic domain (IPR006098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250844 control chromosomes. c.917C>T has been reported in the literature in at least one homozygous individual affected with f Methylmalonic Acidemia and at least one individual from a cohort with diagnosed inborn errors of metabolism (e.g., Worgan_2006, Adhikari_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 16281286). ClinVar contains an entry for this variant (Variation ID: 553978). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 06, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at