Submissions for variant NM_000218.3(KCNQ1):c.1697C>A (p.Ser566Tyr)

dbSNP: rs199472804

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046014	SCV000074027	pathogenic	Long QT syndrome	2024-06-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 566 of the KCNQ1 protein (p.Ser566Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant long QT syndrome (PMID: 15840476, 19716085, 23631430, 28606196, 32421437; Invitae). ClinVar contains an entry for this variant (Variation ID: 53005). 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 with a positive predictive value of 95%. This variant disrupts the p.Ser566 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 22949429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000505737	SCV000234518	likely pathogenic	not provided	2024-10-23	criteria provided, single submitter	clinical testing	Identified in patients with LQTS referred for genetic testing at GeneDx and in published literature; including a patient identified prenatally with congenital LQTS (PMID: 15840476, 23631430, 32421437, 38361570); Variant found to segregate with disease in two affected relatives of a patient with LQTS tested at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19716085, 15840476, 23631430, 19862833, 28606196, 31415974, 32421437, 22949429, 38361570)
Color Diagnostics, LLC DBA Color Health	RCV003591638	SCV004358437	likely pathogenic	Cardiac arrhythmia	2023-03-13	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tyrosine at codon 566 of the KCNQ1 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). This variant is found within a highly conserved region of the C-terminal cytoplasmic domain. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). This variant has been reported in ten individuals from four families affected with long QT syndrome (PMID: 31415974, 32421437, ClinVar SCV000074027.7, SCV000234518.8), another three unrelated individuals suspected of having long QT syndrome (PMID: 15840476, 19716085), and an individual affected with syncope (PMID: 28606196). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Ser566Phe, is considered to be disease causing (ClinVar variation ID 53006), indicating that serine at this position is important for KCNQ1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057618	SCV000089137	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:15840476;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.