ClinVar Miner

Submissions for variant NM_002109.6(HARS1):c.1067G>A (p.Ser356Asn)

gnomAD frequency: 0.00004  dbSNP: rs144322728
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000650140 SCV000771977 uncertain significance Usher syndrome type 3B 2024-09-23 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 356 of the HARS protein (p.Ser356Asn). This variant is present in population databases (rs144322728, gnomAD 0.004%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 29235198). ClinVar contains an entry for this variant (Variation ID: 446301). 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 expected to disrupt HARS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HARS function (PMID: 29235198). 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 RCV004023493 SCV002755226 uncertain significance not specified 2021-11-04 criteria provided, single submitter clinical testing The p.S356N variant (also known as c.1067G>A), located in coding exon 10 of the HARS gene, results from a G to A substitution at nucleotide position 1067. The serine at codon 356 is replaced by asparagine, an amino acid with highly similar properties. This variant was detected in an individual with Charcot-Marie-Tooth disease and in an unaffected parent (Abbott JA et al. Hum Mutat, 2018 03;39:415-432). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic RCV004791505 SCV005411878 uncertain significance not provided 2024-06-14 criteria provided, single submitter clinical testing PS3
Antonellis Laboratory at Michigan, University of Michigan RCV000515536 SCV000611614 uncertain significance Autosomal dominant Charcot-Marie-Tooth disease type 2W no assertion criteria provided in vitro

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