rs200089613
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_012208.4(HARS2):c.1439G>A(p.Arg480His) variant causes a missense change. The variant allele was found at a frequency of 0.000119 in 1,614,080 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).
Frequency
Consequence
NM_012208.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000795 AC: 20AN: 251444Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135908
GnomAD4 exome AF: 0.000127 AC: 185AN: 1461854Hom.: 0 Cov.: 33 AF XY: 0.000111 AC XY: 81AN XY: 727228
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74370
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Reported with a second variant, in trans, in unrelated individuals with bilateral sensorineural hearing loss in published literature (PMID: 31827252); 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: 3440684, 31827252) -
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 480 of the HARS2 protein (p.Arg480His). This variant is present in population databases (rs200089613, gnomAD 0.02%). This missense change has been observed in individual(s) with Perrault syndrome (PMID: 31827252). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 635270). 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 HARS2 protein function. For these reasons, this variant has been classified as Pathogenic. -
Sensorineural hearing loss disorder Pathogenic:1
Likely pathogenic variant in a known hearing loss gene. Seen in three unrelated individuals with hearing loss as a compund heterozygous variant in trans to another likely pathogenic variant. -
Perrault syndrome Pathogenic:1
The p.Arg486His variant in HARS2 (also referred to as p.Arg480His) has been reported in the compound heterozygous state in three individuals with Perrault syndrome, including in two individuals in combination with a likely pathogenic variant (Demain 2020 PMID: 31827252). The variant also segregated with disease in 1 affected relative. This variant has also been reported in ClinVar (Variation ID 635270). It has been identified in 7/68038 of European chromosomes by gnomAD v3.1.2 (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Perrault syndrome. ACMG/AMP Criteria applied: ACMG: PM3_Strong, PP1_Supporting, PP3, PM2_Supporting. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at