Submissions for variant NM_002109.6(HARS1):c.1045G>A (p.Glu349Lys)

dbSNP: rs1371763515

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519456	SCV000620209	uncertain significance	not provided	2017-08-16	criteria provided, single submitter	clinical testing	The E349K variant in the HARS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E349K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E349K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E349K as a variant of uncertain significance.
Invitae	RCV001240270	SCV001413200	uncertain significance	Usher syndrome type 3B	2023-11-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 349 of the HARS protein (p.Glu349Lys). This variant is not present in population databases (gnomAD no frequency). 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: 451496). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.