Submissions for variant NM_000218.3(KCNQ1):c.1903G>A (p.Gly635Arg)

gnomAD frequency: 0.00005  dbSNP: rs199473484

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767093	SCV000234539	uncertain significance	not provided	2023-04-25	criteria provided, single submitter	clinical testing	Reported in association with LQTS and HCM in the published literature; additional clinical details were not provided (Kapplinger et al., 2009; Lopes et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19716085, 25351510, 25854863, 21956039, 22581653, 34930020)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182236	SCV000539463	uncertain significance	not specified	2016-10-20	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only reported in 2-3 probands with LQT, variant aa present in other mammals
Illumina Laboratory Services, Illumina	RCV001108386	SCV001265615	uncertain significance	Long QT syndrome 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001108387	SCV001265616	uncertain significance	Short QT syndrome type 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001108388	SCV001265617	uncertain significance	Jervell and Lange-Nielsen syndrome 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001108389	SCV001265618	uncertain significance	Atrial fibrillation, familial, 3	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001841680	SCV001355493	uncertain significance	Cardiac arrhythmia	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 635 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). To our knowledge, functional studies have not been reported for this variant. An experimental functional study has shown that this variant results in a reduced peak current density (PMID: 34930020). This variant has been reported in two individuals suspected to be affected with long QT syndrome (PMID: 19716085), in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510), and in an individual affected with atrial fibrillation (PMID: 34930020). This variant has been identified in 4/222516 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.
Invitae	RCV001238350	SCV001411155	uncertain significance	Long QT syndrome	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 635 of the KCNQ1 protein (p.Gly635Arg). 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: 19716085). ClinVar contains an entry for this variant (Variation ID: 67062). 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	RCV000767093	SCV002502334	uncertain significance	not provided	2021-09-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498333	SCV002780993	uncertain significance	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-09-02	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057649	SCV000089168	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.