rs774649299
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_015340.4(LARS2):c.1987C>T(p.Arg663Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R663R) has been classified as Likely benign.
Frequency
Consequence
NM_015340.4 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 |
---|---|---|---|---|---|---|---|
LARS2 | NM_015340.4 | c.1987C>T | p.Arg663Trp | missense_variant | 17/22 | ENST00000645846.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LARS2 | ENST00000645846.2 | c.1987C>T | p.Arg663Trp | missense_variant | 17/22 | NM_015340.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251366Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135852
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727230
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
Perrault syndrome 4 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 2021 | - - |
Pathogenic, no assertion criteria provided | research | Reproductive Development, Murdoch Childrens Research Institute | Oct 21, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris | Jan 06, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2023 | Published functional studies suggest this variant is associated with reduced mitochondrial leucyl-tRNA synthase activity (van der Knaap MS et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 30737337, 28708303, 32399598) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at