ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.1640C>T (p.Ala547Val)

gnomAD frequency: 0.00001  dbSNP: rs1473812774
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001057221 SCV001221703 uncertain significance Long QT syndrome 2022-07-25 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably 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. Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 20876384, 22359612). ClinVar contains an entry for this variant (Variation ID: 852580). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 547 of the KCNH2 protein (p.Ala547Val).
Color Diagnostics, LLC DBA Color Health RCV001842603 SCV001352531 uncertain significance Cardiac arrhythmia 2023-05-09 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 547 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant has no significant impact on channel function (PMID: 20876384, 22359612). To our knowledge, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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