Submissions for variant NM_000218.3(KCNQ1):c.328G>A (p.Val110Ile)

gnomAD frequency: 0.00009  dbSNP: rs199472677

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000057658	SCV000050777	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046047	SCV000074060	uncertain significance	Long QT syndrome	2023-12-06	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 110 of the KCNQ1 protein (p.Val110Ile). This variant is present in population databases (rs199472677, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 14661677, 19841300, 21164565). ClinVar contains an entry for this variant (Variation ID: 53034). 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) has been performed at Invitae 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 have shown that this missense change affects KCNQ1 function (PMID: 21164565, 29532034). 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.
GeneDx	RCV000057658	SCV000234562	uncertain significance	not provided	2024-11-19	criteria provided, single submitter	clinical testing	Identified in a patient with LQTS in published literature; however, this patient harbored an additional variant in the KCNH2 gene (PMID: 21164565); Identified in two cases of stillbirth in published literature (PMID: 30615648); Published functional studies suggest a damaging effect via decreased current density and prolonged duration of simulated left ventricular epicardial action potentials, but without affecting cell surface expression (PMID: 30571187, 21164565, 29532034); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14661677, 21164565, 23861362, 22949429, 19841300, 30571187, 29532034, 29021305, 32797034, 22581653, 30615648)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182259	SCV000271877	uncertain significance	not specified	2015-06-02	criteria provided, single submitter	clinical testing	The p.Val110Ile variant in KCNQ1 has not been previously reported in individuals with hearing loss or Jervell and Lange-Nielsen syndrome; however, it has been i dentified in one individual with long QT syndrome (Cordeiro 2010). This variant has also been identified in 8/55006 European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199472677). In vitro functional studies provide some evidence that this variant may impact protein f unction (Cordeiro 2010); however, these types of assays may not accurately repre sent biological function. Computational prediction tools and conservation analy ses suggest that the p.Val110Ile variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Val110Ile variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV000057658	SCV000891944	uncertain significance	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018947	SCV004891491	uncertain significance	Cardiovascular phenotype	2022-02-18	criteria provided, single submitter	clinical testing	The c.328G>A (p.V110I) alteration is located in exon 1 (coding exon 1) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 328, causing the valine (V) at amino acid position 110 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786321	SCV005398166	uncertain significance	Long QT syndrome 1	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 for a condition (27 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as a VUS by multiple clinical diagnostic laboratories and a benign variant based on its allele frequency being greater than published estimates for LQTS disease prevalence (ClinVar, PMID: 23861362). However, this variant has also been reported in two stillbirth cases and one individual with severe LQTS who carried an additional common polymorphism in KCNH2 (PMIDs: 30615648, 21164565). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The mutant transcript expressed in both CHO-KI and HEK293T cells and assessed using patch clamp studies demonstrated normal surface trafficking levels but reduced peak current densities compared to the WT transcript (PMIDs: 21164565, 29532034). It should be noted that the same reduction in peak current density was also observed in CHO-KI cells carrying a KCNH2 common polymorphism (PMID: 21164565). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057658	SCV000089177	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:14661677;PMID:19841300;PMID:21164565).