ClinVar Miner

Submissions for variant NM_002109.6(HARS1):c.220G>A (p.Glu74Lys) (rs774017621)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000650145 SCV000771982 uncertain significance Usher syndrome, type 3B 2019-05-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 74 of the HARS protein (p.Glu74Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs774017621, ExAC 0.02%). This variant has not been reported in the literature in individuals with HARS-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001071 SCV001158201 uncertain significance not specified 2019-03-02 criteria provided, single submitter clinical testing The p.Glu74Lys variant (rs774017621) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.002 percent (identified on 4 out of 251,482 chromosomes) and has been reported to the ClinVar database (Variation ID: 540198). The glutamic acid at position 74 is weakly conserved and computational analyses of the effects of the p.Glu74Lys variant on protein structure and function is conflicting (SIFT: tolerated, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Glu74Lys variant with certainty.

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