Submissions for variant NM_000238.4(KCNH2):c.1325C>T (p.Ala442Val)

dbSNP: rs1554426225

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000536145	SCV000627420	uncertain significance	Long QT syndrome	2017-06-07	criteria provided, single submitter	clinical testing	In summary, this variant has uncertain impact on KCNH2 function. The available evidence is currently insufficient to determine its role 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a KCNH2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 442 of the KCNH2 protein (p.Ala442Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768002	SCV000898771	uncertain significance	Short QT syndrome type 1; Long QT syndrome 2	2021-11-11	criteria provided, single submitter	clinical testing	KCNH2 NM_000238.3 exon 6 p.Ala442Val (c.1325C>T): This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar (Variation ID:456885). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.