Submissions for variant NM_002109.6(HARS1):c.256C>T (p.Arg86Cys)

gnomAD frequency: 0.00001  dbSNP: rs775758650

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics, Royal Melbourne Hospital	RCV002225157	SCV002503645	uncertain significance	Autosomal dominant Charcot-Marie-Tooth disease type 2W	2021-02-26	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace arginine with cysteine at codon 86 of the HARS1 protein (p.(Arg86Cys)). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the histidyl-tRNA synthetase catalytic domain. There is a large physicochemical difference between arginine and cysteine. The variant is present in a large population cohort at a frequency of 0.003% (rs775758650, 7/251,490 alleles, 0 homozygotes in gnomAD v2.1), and has not been reported in the relevant medical literature or databases. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 4/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002236390	SCV002507897	uncertain significance	Usher syndrome type 3B	2024-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 86 of the HARS protein (p.Arg86Cys). This variant is present in population databases (rs775758650, gnomAD 0.006%). 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: 1678556). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002225157	SCV005398403	uncertain significance	Autosomal dominant Charcot-Marie-Tooth disease type 2W	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function is a known mechanism of disease in this gene, and is associated with multisystemic ataxic syndrome (PMID: 32333447), while dominant negative is a suggested mechanism associated with Charcot-Marie-Tooth disease, axonal, type 2W (CMT) (MIM#616625) (PMID: 26072516). While studies have shown missense variants causing CMT to have a loss of function effect, dominant negative is a more likely mechanism and is yet to be functionally proven (PMID: 32940403). (I) 0108 - This gene is associated with both recessive and dominant disease. Missense variants have been reported to cause CMT, while an association to recessive Usher syndrome is disputed (ClinGen, OMIM, PMID: 26072516). Individuals with biallelic variants have been reported to cause a recessive multisystemic ataxic syndrome (PMID: 32333447). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0219 - This variant is non-coding in an alternative transcript. This variant is protein coding in the ClinVar predominant transcript (NM_002109.6), but is non-coding in another highly expressed transcript (GTex). (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (7 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (17 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated histidyl-tRNA synthetase domain (Pfam, DECIPHER). (I) 0709 - Another missense variant has limited previous evidence for being benign. This alternative missense variant (p.Arg86His) has a lower Grantham score, and has been described as non-causative due to non segregation in a family with CMT (PMID: 24354524). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign