Submissions for variant NM_000218.3(KCNQ1):c.1892C>G (p.Pro631Arg)

gnomAD frequency: 0.00002  dbSNP: rs1432436411

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001843080	SCV001345964	uncertain significance	Cardiac arrhythmia	2021-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 631 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/188540 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.
GeneDx	RCV001751321	SCV001996495	uncertain significance	not provided	2019-09-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Ambry Genetics	RCV002411684	SCV002719175	uncertain significance	Cardiovascular phenotype	2020-07-06	criteria provided, single submitter	clinical testing	The p.P631R variant (also known as c.1892C>G), located in coding exon 16 of the KCNQ1 gene, results from a C to G substitution at nucleotide position 1892. The proline at codon 631 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in an individual with long QT syndrome (Krahn AD et al. Circ Arrhythm Electrophysiol, 2012 Oct;5:933-40). It was also identified in a child with congenital erythropoietic porphyria with no information provided regarding cardiac status or evaluations provided (Wang J et al. Genome Med, 2015 Jul;7:77). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002560809	SCV003033266	uncertain significance	Long QT syndrome	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 631 of the KCNQ1 protein (p.Pro631Arg). This variant is present in population databases (no rsID available, gnomAD 0.008%). 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: 921471). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	RCV002560809	SCV004836501	uncertain significance	Long QT syndrome	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 631 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/188540 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.