ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1519C>T (p.Pro507Ser) (rs794728371)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586117 SCV000234099 uncertain significance not provided 2016-11-18 criteria provided, single submitter clinical testing The Pro507Ser variant in the KCNH2 gene has not been reported as a disease-causing pathogenic variant or as a benign polymorphism to our knowledge. Pro507Ser results in a non-conservative amino acid substitution of a nonpolar Proline with a polar Serine at a position in the transmembrane domain that is highly conserved across species. In silico analysis predicts Pro507Ser is probably damaging to the protein structure/function. Variants in a nearby residue (Asp501Asn, Asp501Gly, Asp501His) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. In addition, the Pro507Ser variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Pro507Ser is a good candidate for a pathogenic variant. The variant is found in LQT panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000586117 SCV000696018 uncertain significance not provided 2017-08-25 criteria provided, single submitter clinical testing Variant summary: The KCNH2 c.1519C>T (p.Pro507Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense change in the ion transport domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121202 control chromosomes (ExAC). One clinical diagnostic laboratory has classified this variant as one of uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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