ClinVar Miner

Submissions for variant NM_012208.4(HARS2):c.697C>T (p.Arg233Cys) (rs749799529)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767024 SCV000251611 uncertain significance not provided 2017-11-03 criteria provided, single submitter clinical testing p.Arg233Cys (CGT>TGT): c.697 C>T in exon 7 of the HARS2 gene (NM_012208.2). The R233C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R233C 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. This substitution occurs at a position that is moderately conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, multiple in-silico splice prediction models predict that the c.697 C>T nucleotide substitution, responsible for R233C, destroys or damages the natural splice acceptor site and results in the increased use of a downstream cryptic splice site which would be expected to result in abnormal gene splicing. However, the true effect of c.697 C>T on splicing in vivo is not known without functional studies. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000199488 SCV000271838 uncertain significance not specified 2016-05-01 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg233Cys variant in HARS2 has been reported by our laboratory in one individual with hea ring loss who was compound heterozygous for a second variant of uncertain signif icance in the HARS2 gene (this family). This variant has been identified in 1/6 6456 European chromosomes and 1/16468 South Asian chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is not high enough to rul e out a pathogenic role. Computational prediction tools suggest that the p.Arg23 3Cys variant may impact the protein, though this information is not predictive e nough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg233Cys variant is uncer tain.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000767024 SCV001500369 uncertain significance not provided 2020-07-01 criteria provided, single submitter clinical testing
OMIM RCV001261944 SCV001439295 pathogenic Perrault syndrome 2 2020-10-26 no assertion criteria provided literature only

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