Submissions for variant NM_000218.3(KCNQ1):c.1663C>A (p.Arg555Ser)

dbSNP: rs120074185

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479287	SCV000565095	likely pathogenic	not provided	2020-03-11	criteria provided, single submitter	clinical testing	Reported in an individual referred for LQTS genetic testing (Kapplinger et al., 2009); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); At the protein level, in silico analysis supports that this missense variant has a deleterious effect on protein structure/function; At the mRNA level, in silico analysis suggests this variant may impact gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 15746441, 25854863, 19716085, 28606196, 32383558)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001226497	SCV001398812	pathogenic	Long QT syndrome	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 555 of the KCNQ1 protein (p.Arg555Ser). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg555 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2313012, 9386136, 14998624, 22949429, 23098067). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 67046). This missense change has been observed in individuals with long QT syndrome (PMID: 19716085, 32383558; Invitae). 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.
Color Diagnostics, LLC DBA Color Health	RCV003591657	SCV004358433	likely pathogenic	Cardiac arrhythmia	2023-09-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 555 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). Splice site prediction tools suggest that this variant may impact RNA splicing. This variant is found within a highly conserved region of C-terminal cytoplasmic domain. Rare nontruncating 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 two individuals suspected of having long QTS syndrome (PMID: 19716085, 32383558). This variant has also been observed either in the homozygous or compound heterozygous state in two unrelated individuals affected with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 28606196, 32383558), indicating that this variant contributes to disease. Different missense variants occurring at the same codon, p.Arg555Cys and p.Arg555His, are known to be pathogenic (Clinvar variation ID 41835, 173188), indicating that arginine at this position is important for KCNQ1 protein function. This variant has been identified in 2/179696 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV001226497	SCV004831341	likely pathogenic	Long QT syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 555 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). Splice site prediction tools suggest that this variant may impact RNA splicing. This variant is found within a highly conserved region of C-terminal cytoplasmic domain. Rare nontruncating 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 two individuals suspected of having long QTS syndrome (PMID: 19716085, 32383558). This variant has also been observed either in the homozygous or compound heterozygous state in two unrelated individuals affected with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 28606196, 32383558), indicating that this variant contributes to disease. Different missense variants occurring at the same codon, p.Arg555Cys and p.Arg555His, are known to be pathogenic (Clinvar variation ID 41835, 173188), indicating that arginine at this position is important for KCNQ1 protein function. This variant has been identified in 2/179696 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000057612	SCV004848446	likely pathogenic	Congenital long QT syndrome	2023-06-01	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786336	SCV005398493	pathogenic	Long QT syndrome 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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 known to be associated with both recessive and dominant disease. JLNS 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 arginine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (2 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated KCNQ channel domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. The p.(Arg555Cys) and p.(Arg555His) variants have been classified as likely pathogenic and pathogenic by multiple clinical diagnostic laboratories (ClinVar; PMID: 19716085)). However, it should also be noted that the p.(Arg555Leu) variant has been classified as a VUS by Invitae. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by clinical diagnostic laboratories (GeneDx, VCGS) and has been identified in multiple individuals with Long QT and as homozygous or compound heterozygous in individuals with JLNS (PMIDs: 19716085, 28606196, 32383558). However, it should also be noted that this variant has been classified as a VUS by Invitae. (SP) 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
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057612	SCV000089131	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.