ClinVar Miner

Submissions for variant NM_001127453.2(GSDME):c.712C>T (p.Arg238Ter)

gnomAD frequency: 0.00032  dbSNP: rs200758965
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000216130 SCV000271630 uncertain significance not specified 2016-02-26 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg238X varia nt in DFNA5 has not been previously reported in individuals with hearing loss, b ut has been identified in 0.4% (27/6614) of Finnish chromosomes by the Exome Agg regation consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200758965). T his nonsense variant leads to a premature termination codon at position 238, whi ch is predicted to lead to a truncated or absent protein. However, only variants resulting in altered splicing and skipping of exon 8 have been reported to be c ausative for hearing loss through a gain of function mechanism of disease (Van L aer 2004). The p.Arg238X variant is located in exon 6 of DFNA5 and is expected t o result in loss of function (LoF), which is not a known mechanism of hearing lo ss in this gene. In fact, a frameshift variant in DFNA5 has been reported in mem bers of an Iranian family, in which the variant did not segregate with the heari ng loss (Van Laer 2007). In summary, while the clinical significance of the p.Ar g238X variant is uncertain, its frequency in the Finnish population and the lack of evidence supporting a LoF mechanism for hearing loss in DFNA5 suggests it is more likely to be benign.
GeneDx RCV000767142 SCV000569025 uncertain significance not provided 2022-04-11 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000767142 SCV001041550 likely benign not provided 2023-12-24 criteria provided, single submitter clinical testing

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