Submissions for variant NM_000218.3(KCNQ1):c.590C>T (p.Pro197Leu)

gnomAD frequency: 0.00002  dbSNP: rs200108320

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171669	SCV000055278	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000171669	SCV000234393	uncertain significance	not provided	2022-10-03	criteria provided, single submitter	clinical testing	Reported in a study examining the cost-effectiveness of genetic testing in inherited heart disease, although clinical information was not provided (Sabater-Molina et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31518351, 27153395, 29197658, 30571187, 34426522, 29532034, 32048431)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000171669	SCV000604067	uncertain significance	not provided	2017-05-05	criteria provided, single submitter	clinical testing	The p.Pro197Leu variant (rs200108320) has been previously identified in several cohorts of cardiomyopathy patients (Ng 2013, Sabater-Molina 2013, Maxwell 2016); however, no additional clinical details or segregation data were provided. This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 191476). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish European populations of 0.011% (identified in 12 out of 111,358 chromosomes). The proline at codon 197 is highly conserved considering 8 species up to Ciona intestinalis (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on KCNQ1 protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.Pro197Leu variant cannot be determined with certainty.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631621	SCV000752703	uncertain significance	Long QT syndrome	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 197 of the KCNQ1 protein (p.Pro197Leu). This variant is present in population databases (rs200108320, gnomAD 0.01%). 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: 191476). 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 with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 29532034, 30571187). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000171669	SCV001148150	uncertain significance	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842520	SCV001350480	uncertain significance	Cardiac arrhythmia	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 197 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). Functional studies have shown that the mutant protein exhibits partially reduced cell surface expression but normal or increased potassium channel activity, which is inconsistent with a mutation causing long QT syndrome (PMID: 29532034, 30571187). This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/249032 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.
Ambry Genetics	RCV002354427	SCV002649567	uncertain significance	Cardiovascular phenotype	2023-11-14	criteria provided, single submitter	clinical testing	The p.P197L variant (also known as c.590C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 590. The proline at codon 197 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485097	SCV002793806	uncertain significance	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-08-13	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV000631621	SCV004022089	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PM1, PP3
All of Us Research Program, National Institutes of Health	RCV000631621	SCV004838766	uncertain significance	Long QT syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 197 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). Functional studies have shown that the mutant protein exhibits partially reduced cell surface expression but normal or increased potassium channel activity, which is inconsistent with a mutation causing long QT syndrome (PMID: 29532034, 30571187). This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/249032 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.
Clinical Genetics, Academic Medical Center	RCV000171669	SCV001924198	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000171669	SCV001927079	uncertain significance	not provided		no assertion criteria provided	clinical testing