Submissions for variant NM_000218.3(KCNQ1):c.1598G>A (p.Arg533Gln)

gnomAD frequency: 0.00001  dbSNP: rs574321120

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000513565	SCV000608577	uncertain significance	not provided	2017-02-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841404	SCV001355513	uncertain significance	Cardiac arrhythmia	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 533 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNQ1-related disorders in the literature. This variant has been identified in 3/170478 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000513565	SCV002502993	uncertain significance	not provided	2021-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002404324	SCV002707812	uncertain significance	Cardiovascular phenotype	2024-06-12	criteria provided, single submitter	clinical testing	The p.R533Q variant (also known as c.1598G>A), located in coding exon 13 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1598. The arginine at codon 533 is replaced by glutamine, an amino acid with highly 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.
Dept of Medical Biology, Uskudar University	RCV003318379	SCV004022051	likely pathogenic	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PS2_Moderate, PM1_Supporting, PM2, PP3
Invitae	RCV003318379	SCV004679691	uncertain significance	Long QT syndrome	2023-09-21	criteria provided, single submitter	clinical testing	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. 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. 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: 444243). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 533 of the KCNQ1 protein (p.Arg533Gln).
All of Us Research Program, National Institutes of Health	RCV003318379	SCV004836465	uncertain significance	Long QT syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 533 of the KCNQ1 protein. Computational prediction tool 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 not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/170478 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.