1-45508982-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_015506.3(MMACHC):c.616C>T(p.Arg206Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,050 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_015506.3 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 |
---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.616C>T | p.Arg206Trp | missense_variant | 4/4 | ENST00000401061.9 | |
MMACHC | NM_001330540.2 | c.445C>T | p.Arg149Trp | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.616C>T | p.Arg206Trp | missense_variant | 4/4 | 2 | NM_015506.3 | P1 | |
MMACHC | ENST00000616135.1 | c.445C>T | p.Arg149Trp | missense_variant | 4/5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249530Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135378
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727244
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Cobalamin C disease Pathogenic:5Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 206 of the MMACHC protein (p.Arg206Trp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 16311595, 20610126, 20631720, 26149271). 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: 203832). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC protein function. This variant disrupts the p.Arg206 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30157807). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 02, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Apr 05, 2024 | The MMACHC c.616C>T (p.Arg206Trp) variant has been reported in at least four individuals in the compound heterozygous state affected with methylmalonic aciduria and homocystinuria, cblC type (Frattini D et al., PMID: 20610126; Lerner-Ellis JP et al., PMID: 16311595; Liu MY et al., PMID: 20631720; Zhong Y et al., PMID: 26149271). Another variant in the same codon, c.617G>A (p.Arg206Gln), has been reported in affected individuals and is considered pathogenic (Hu S et al., PMID: 30157807, ClinVar Variation ID: 848845). This variant is only observed on 1/249,530 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to MMACHC function. This variant has been reported in the ClinVar database as a germline pathogenic variant by three groups, likely pathogenic by one group and a variant of uncertain significance by one group. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 02, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at