Submissions for variant NM_000218.3(KCNQ1):c.1571T>G (p.Val524Gly)

dbSNP: rs199472790

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046000	SCV000074013	pathogenic	Long QT syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 524 of the KCNQ1 protein (p.Val524Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant long QT syndrome (PMID: 14678125, 15840476, 17470695, 22949429). This variant has been reported in individual(s) with autosomal recessive long QT syndrome without hearing loss typically associated with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 23392653); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 52994). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000182201	SCV000234504	pathogenic	not provided	2022-09-08	criteria provided, single submitter	clinical testing	Identified in patients with LQTS referred for genetic testing at GeneDx, and in the published literature (Zareba et al., 2003; Tester et al., 2005; Kapplinger et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies with low cytometry of V524G-transfected HEK293 cells showed significantly reduced surface trafficking compared to wild-type (Kanner et al., 2020); 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: 23392653, 25525159, 15466642, 15840476, 19716085, 17470695, 19841300, 22949429, 33198487, 23728945, 22581653, 14678125, 33169015)
Ambry Genetics	RCV004017349	SCV004849043	uncertain significance	Cardiovascular phenotype	2019-06-07	criteria provided, single submitter	clinical testing	The c.1571T>G (p.V524G) alteration is located in exon 12 (coding exon 12) of the KCNQ1 gene. This alteration results from a T to G substitution at nucleotide position 1571, causing the valine (V) at amino acid position 524 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057599	SCV000089118	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:14678125;PMID:15466642;PMID:15840476;PMID:19716085;PMID:19841300;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Genetics, Academic Medical Center	RCV000182201	SCV001922124	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000182201	SCV001956877	pathogenic	not provided		no assertion criteria provided	clinical testing