Submissions for variant NM_000218.3(KCNQ1):c.1621G>A (p.Val541Ile)

gnomAD frequency: 0.00002  dbSNP: rs199472796

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767088	SCV000234511	uncertain significance	not provided	2020-03-30	criteria provided, single submitter	clinical testing	Reported in at least one individual in association with LQTS (Kapplinger et al., 2009; Kapplinger et al., 2015); Reported in ClinVar as a variant of uncertain significance by several other clinical laboratories (ClinVar Variant ID#67043; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19716085, 25854863, 22581653, 29021305, 32048431, 32233023)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182208	SCV000539462	uncertain significance	not specified	2016-07-26	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: Reported in 1 LQT proband; ClinVar: Path by GeneDx
Color Diagnostics, LLC DBA Color Health	RCV001841673	SCV000904591	uncertain significance	Cardiac arrhythmia	2023-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 541 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has been identified in 5/184336 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	RCV001040145	SCV001203706	uncertain significance	Long QT syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 541 of the KCNQ1 protein (p.Val541Ile). 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 long QT syndrome (LQTS) (PMID: 19716085; Invitae). ClinVar contains an entry for this variant (Variation ID: 67043). 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%. 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	RCV000767088	SCV002501061	uncertain significance	not provided	2022-01-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000767088	SCV002541116	uncertain significance	not provided	2021-09-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298106	SCV003997453	uncertain significance	Cardiovascular phenotype	2021-03-22	criteria provided, single submitter	clinical testing	The c.1621G>A (p.V541I) alteration is located in exon 13 (coding exon 13) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 1621, causing the valine (V) at amino acid position 541 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001040145	SCV004836467	uncertain significance	Long QT syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 541 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has been identified in 5/184336 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057606	SCV000089125	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.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656140	SCV000678334	uncertain significance	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001089522	SCV001244875	likely pathogenic	Long QT syndrome 1	2019-07-22	flagged submission	clinical testing