Submissions for variant NM_000218.3(KCNQ1):c.1726G>A (p.Val576Ile)

gnomAD frequency: 0.00002  dbSNP: rs750409379

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767090	SCV000234377	uncertain significance	not provided	2018-10-30	criteria provided, single submitter	clinical testing	The V576I variant in the KCNQ1 gene has been reported previously in one individual with LQTS (Mullaly J et al., 2013). In addition, V576I has been reported in one individual with a swimming-induced syncopal event and a paternal family history of sudden unexplained death who also harbors the R594P mutation in the KCNQ1 gene (Giudicessi J et al., 2013). Segregation analysis in this family showed that the V576I variant was inherited from the asymptomatic mother and that the origin of the R594P mutation is unknown as the father was unavailable for testing (Giudeicessi et al., 2013). The V576I variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, missense mutations in nearby residues (S571L, F573L, R583G, R583C, R583H) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson P et al., 2014), supporting the functional importance of this region of the protein. Nevertheless, the V576I variant is a conservative amino acid substitution that occurs at a position that is very poorly conserved across species, with Isoleucine present at this residue in greater than 10 rodent species. Consequently, in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182074	SCV000270311	likely benign	not specified	2015-08-13	criteria provided, single submitter	clinical testing	p.Val576Ile in exon 14 of KCNQ1: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 13 mammals have an Ile at this position despite high nearby amino acid con servation. In addition, computational prediction tools do not suggest a high lik elihood of impact to the protein. It has also been identified in 5/65838 Europea n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org). Although this variant has been reported in 2 individuals with LQTS (1 with intact hearing who carried a second likely pathogenic variant) (Mullally 20 13, Giudicessi 2013), based on the lack of conservation at this position, this v ariant is likely benign.
Mendelics	RCV000988474	SCV001138207	benign	Long QT syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001048069	SCV001212058	uncertain significance	Long QT syndrome	2023-12-11	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 576 of the KCNQ1 protein (p.Val576Ile). This variant is present in population databases (rs750409379, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of KCNQ1-related conditions (PMID: 18752142, 23174487, 23392653). ClinVar contains an entry for this variant (Variation ID: 200813). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV001842868	SCV001350479	likely benign	Cardiac arrhythmia	2018-11-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399648	SCV002712495	uncertain significance	Cardiovascular phenotype	2023-07-12	criteria provided, single submitter	clinical testing	The p.V576I variant (also known as c.1726G>A), located in coding exon 14 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1726. The valine at codon 576 is replaced by isoleucine, an amino acid with highly similar properties, and is located in the C-terminal, cytoplasmic region of the protein. This variant co-occurred with a second KCNQ1 variant in an individual with long QT syndrome and intact hearing whose mother, with a normal QTc interval, carried only the p.V576I variant; however, the father was unavailable for testing (Giudicessi JR et al. Circ Cardiovasc Genet, 2013 Apr;6:193-200). This variant has also been detected in long QT syndrome cohorts; however, details were limited (Mullally J et al. Heart Rhythm, 2013 Mar;10:378-82; Berge KE et al. Scand. J. Clin. Lab. Invest. 2008 ;68(5):362-8). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
New York Genome Center	RCV003227700	SCV003925346	uncertain significance	Atrial fibrillation, familial, 3; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2022-04-06	criteria provided, single submitter	clinical testing	The c.1726G>A p.(Val576Ile) variant in KCNQ1 has previously been reported heterozygous in an individual with long QT syndrome [PMID: 23174487] and compound heterozygous in an individual with Jervell and Lange-Nielsen syndrome without deafness [PMID: 23392653]. This variant has been deposited in ClinVar [ClinVar ID:200813] as Variant of Uncertain Significance, Likely benign, and Benign. The 1726G>A variant is observed in 24 alleles (~0.003% MAF with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases.The c.1726G>A variant is located in exon 14 of this 16-exon gene and predicted to replace a poorly conserved valine amino acid with isoleucine at position 576. In silico predictions are inconclusive of the variant's effect (CADD v1.6 = 17.03, REVEL = 0.622); however, there are no functional studies to support or refute these predictions. Based on available evidence this c.1726G>A p.(Val576Ile) variant identified in KCNQ1 is classified as a Variant of Uncertain Significance.