Submissions for variant NM_000218.3(KCNQ1):c.1876G>A (p.Gly626Ser)

gnomAD frequency: 0.00001  dbSNP: rs199472821

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182325	SCV000234628	uncertain significance	not provided	2018-04-30	criteria provided, single submitter	clinical testing	The G626S variant of uncertain significance in the KCNQ1 gene has previously been reported in individuals referred for LQTS genetic testing, although no specific clinical information was provided (Tester et al., 2005; Kapplinger et al., 2009). This variant was also identified in one French infant with sudden infant death syndrome, as well as in this patient's asymptomatic mother (Millat et al., 2006; Millat et al., 2009). The G626S variant is not observed in large population cohorts (Lek et al., 2016). The G626S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics	RCV000620378	SCV000737763	uncertain significance	Cardiovascular phenotype	2016-10-24	criteria provided, single submitter	clinical testing	The c.1876G>A (p.G626S) alteration is located in exon 16 (coding exon 16) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 1876, causing the glycine (G) at amino acid position 626 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852972	SCV002202691	uncertain significance	Long QT syndrome	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 626 of the KCNQ1 protein (p.Gly626Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of KCNQ1-related conditions (PMID: 15840476, 19322600). ClinVar contains an entry for this variant (Variation ID: 53022). 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 not expected to disrupt KCNQ1 protein function. 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000182325	SCV002503024	uncertain significance	not provided	2021-11-20	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	RCV000755677	SCV004024190	uncertain significance	Long QT syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003591640	SCV004358447	uncertain significance	Cardiac arrhythmia	2022-11-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 626 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant has no significant impact on channel peak current density (PMID: 34930020). This variant has been reported in an individual affected with sudden infant death syndrome (PMID: 16922724), in an individual suspected of having long QT syndrome (PMID: 15840476), and in a few unaffected individuals (PMID: 19322600, 34930020). This variant has been identified in 2/179998 chromosomes 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182325	SCV004848091	uncertain significance	not provided	2022-06-30	criteria provided, single submitter	clinical testing	The p.Gly626Ser variant in KCNQ1 has been reported in 1 individual with long QT syndrome (Tester 2005 PMID: 15840476) and in case of infant sudden death, but was also present the asymptomatic mother (Millat 2006 PMID: 16922724). It has also been identified in 0.004% (1/24468) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, BP4.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057647	SCV000089166	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:16922724;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755677	SCV000883085	pathogenic	Long QT syndrome 1	2018-11-21	flagged submission	clinical testing