Submissions for variant NM_000218.3(KCNQ1):c.1747C>T (p.Arg583Cys)

gnomAD frequency: 0.00002  dbSNP: rs17221854

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182219	SCV000234522	likely pathogenic	not provided	2025-03-07	criteria provided, single submitter	clinical testing	Observed in individuals with LQTS in published literature (PMID: 10973849, 24606995); Published functional studies demonstrate a damaging effect on the ion current of the potassium channel (PMID: 11997281); 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: 15851285, 14760488, 22581653, 15140888, 14661677, 21699863, 11997281, 19995808, 24606995, 10973849, 27690226, 32893267, 24190995)
Fulgent Genetics, Fulgent Genetics	RCV000762837	SCV000893196	likely pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2018-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000182219	SCV002016773	likely pathogenic	not provided	2020-08-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851606	SCV002258869	likely pathogenic	Long QT syndrome	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 583 of the KCNQ1 protein (p.Arg583Cys). This variant is present in population databases (rs17221854, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 10973849, 11997281, 32893267; external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 3142). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 11997281, 24190995, 27690226). This variant disrupts the p.Arg583 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 15851171), which suggests that this may be a clinically significant amino acid residue. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000182219	SCV004033115	likely pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	KCNQ1: PM1, PM5, PS4:Moderate
Color Diagnostics, LLC DBA Color Health	RCV003591618	SCV004358439	uncertain significance	Cardiac arrhythmia	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 583 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). Functional studies have shown that this variant changes channel function (PMID: 11997281, 27690226). This variant has been reported in individuals affected with or suspected of having long QT syndrome (PMID: 10973849, 11997281, 24606995, 32893267). This variant has been identified in 4/251016 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.
Ambry Genetics	RCV004018545	SCV004891484	uncertain significance	Cardiovascular phenotype	2022-07-12	criteria provided, single submitter	clinical testing	The c.1747C>T (p.R583C) alteration is located in exon 15 (coding exon 15) of the KCNQ1 gene. This alteration results from a C to T substitution at nucleotide position 1747, causing the arginine (R) at amino acid position 583 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001851606	SCV005426384	uncertain significance	Long QT syndrome	2024-08-06	criteria provided, single submitter	clinical testing
OMIM	RCV000003291	SCV000023449	pathogenic	Long QT syndrome 1	2002-04-23	no assertion criteria provided	literature only
OMIM	RCV000003292	SCV000023450	risk factor	Acquired susceptibility to long QT syndrome 1	2002-04-23	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057628	SCV000089147	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:10973849;PMID:11997281;PMID:14760488). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GenomeConnect, ClinGen	RCV001824559	SCV002075210	not provided	KCNQ1-related disorder		no assertion provided	phenotyping only	Variant classified as likely pathogenic on 2021-05-23 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.