rs121908834
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_003680.4(YARS1):c.586G>C(p.Glu196Gln) 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. 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. E196G) has been classified as Uncertain significance.
Frequency
Consequence
NM_003680.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
YARS1 | NM_003680.4 | c.586G>C | p.Glu196Gln | missense_variant | 5/13 | ENST00000373477.9 | |
YARS1 | XM_011542347.3 | c.-45G>C | 5_prime_UTR_variant | 3/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
YARS1 | ENST00000373477.9 | c.586G>C | p.Glu196Gln | missense_variant | 5/13 | 1 | NM_003680.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease dominant intermediate C Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 26, 2023 | Experimental studies have shown that this missense change affects YARS function (PMID: 26257172). 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 not expected to disrupt YARS protein function. ClinVar contains an entry for this variant (Variation ID: 243071). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type I (PMID: 26257172; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 196 of the YARS protein (p.Glu196Gln). This variant disrupts the p.Glu196 amino acid residue in YARS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16429158, 19561293). 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 | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Aug 18, 2015 | Likely pathogenic based on segregation with the phenotype in a pedigree with dominant intermediate CMT, and based on conservation and prediction scores (Phylop, Polyphen, SIFT, MutationTaster). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at