ClinVar Miner

Submissions for variant NM_002109.6(HARS1):c.1407G>C (p.Gln469His)

gnomAD frequency: 0.00001  dbSNP: rs1405966952
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001324364 SCV001515316 uncertain significance Usher syndrome type 3B 2024-10-23 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 469 of the HARS protein (p.Gln469His). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with HARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1024208). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HARS protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV004035130 SCV002754644 uncertain significance not specified 2020-07-28 criteria provided, single submitter clinical testing The p.Q469H variant (also known as c.1407G>C), located in coding exon 12 of the HARS gene, results from a G to C substitution at nucleotide position 1407. The glutamine at codon 469 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV003322879 SCV004028214 uncertain significance not provided 2023-02-15 criteria provided, single submitter clinical testing 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; Has not been previously published as pathogenic or benign to our knowledge

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