Submissions for variant NM_000218.3(KCNQ1):c.839T>A (p.Val280Glu)

dbSNP: rs199473462

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046143	SCV000074156	likely pathogenic	Long QT syndrome	2023-03-10	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 280 of the KCNQ1 protein (p.Val280Glu). This missense change has been observed in individuals with long QT syndrome (PMID: 16414944, 19716085, 23158531; Invitae). ClinVar contains an entry for this variant (Variation ID: 53117). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001841654	SCV001345176	likely pathogenic	Cardiac arrhythmia	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glutamic acid at codon 280 of the KCNQ1 protein. This variant is found within a highly conserved region of the transmembrane domain S5. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a large reduction of channel peak current density when expressed in Chinese hamster ovary cells (PMID: 34930020). This variant has been reported in at least three unrelated individuals affected with long QT syndrome (PMID: 16414944, 23158531, 32893267, 34930020, ClinVar SCV000074156.6) and in two individuals suspected of long QT syndrome (PMID: 19716085, 21956039). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057777	SCV000089296	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16414944;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.