7-30599995-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3
The ENST00000389266.8(GARS1):c.373G>C(p.Glu125Gln) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E125G) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000389266.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GARS1 | NM_002047.4 | c.373G>C | p.Glu125Gln | missense_variant | 3/17 | ENST00000389266.8 | NP_002038.2 | |
GARS1 | NM_001316772.1 | c.211G>C | p.Glu71Gln | missense_variant | 3/17 | NP_001303701.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GARS1 | ENST00000389266.8 | c.373G>C | p.Glu125Gln | missense_variant | 3/17 | 1 | NM_002047.4 | ENSP00000373918 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 01, 2018 | A different missense substitution at this codon (p.Glu125Lys) has been determined to be pathogenic (PMID: 25356970). This suggests that the glutamic acid residue is critical for GARS protein function and that other missense substitutions at this position may also be pathogenic. This sequence change replaces glutamic acid with glutamine at codon 125 of the GARS protein (p.Glu125Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GARS-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at