Submissions for variant NM_000218.3(KCNQ1):c.1925G>T (p.Cys642Phe)

gnomAD frequency: 0.00001  dbSNP: rs1456989889

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001843257	SCV001351956	uncertain significance	Cardiac arrhythmia	2023-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 642 of the KCNQ1 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. This variant is found within a highly conserved C-terminus region (a.a. 608-676). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 1 individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002559916	SCV003476741	uncertain significance	Long QT syndrome	2024-05-13	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 642 of the KCNQ1 protein (p.Cys642Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 924413). 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 with a negative 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.
All of Us Research Program, National Institutes of Health	RCV002559916	SCV004836507	uncertain significance	Long QT syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 642 of the KCNQ1 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. This variant is found within a highly conserved C-terminus region (a.a. 608-676). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 1 individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has not been identified 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789441	SCV005398744	uncertain significance	Long QT syndrome 1	2023-07-16	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 2 (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome 1 (LQTS, MIM#192500), familial atrial fibrillation 3 (MIM#607554) as well as Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is associated with both recessive and dominant disease. JLNS (MIM#220400) is characterised 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, PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 1 heterozygote, 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) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Cys642Arg) and p.(Cys642Trp) have been reported as VUS by clinical testing laboratories (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS in an adult who reported no personal history of heart disease (ClinVar, personal communication). It has also been identified in a HCM cohort (PMID: 25351510). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign