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

gnomAD frequency: 0.00001  dbSNP: rs749799529

Total submissions: 5

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, Mass General Brigham 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 Center for Human Genetics Tuebingen	RCV000767024	SCV001500369	uncertain significance	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV000767024	SCV002306774	uncertain significance	not provided	2021-11-15	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 214546). This variant is also known as p.Arg208Cys. This missense change has been observed in individual(s) with deafness (PMID: 31486067). This variant is present in population databases (rs749799529, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 233 of the HARS2 protein (p.Arg233Cys).
OMIM	RCV001261944	SCV001439295	pathogenic	Perrault syndrome 2	2020-10-26	no assertion criteria provided	literature only