Submissions for variant NM_000218.3(KCNQ1):c.1109C>T (p.Ala370Val)

gnomAD frequency: 0.00001  dbSNP: rs775362401

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001841958	SCV000908168	uncertain significance	Cardiac arrhythmia	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 370 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 been reported in an individual affected with sudden death (PMID: 26228265). This variant has been identified in 41/282548 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing. However, available evidence is insufficient to rule out the pathogenicity of this variant conclusively. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203576	SCV001374749	uncertain significance	Long QT syndrome	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 370 of the KCNQ1 protein (p.Ala370Val). This variant is present in population databases (rs775362401, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with sudden death (PMID: 26228265). ClinVar contains an entry for this variant (Variation ID: 629754). 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%. 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.
GeneDx	RCV001574714	SCV001801581	uncertain significance	not provided	2020-04-02	criteria provided, single submitter	clinical testing	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: 32383558, 29197658, 26228265)
Ambry Genetics	RCV002440609	SCV002744912	benign	Cardiovascular phenotype	2022-08-05	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002501006	SCV002814905	uncertain significance	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-10-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001203576	SCV004836381	uncertain significance	Long QT syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 370 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 been reported in an individual affected with sudden death (PMID: 26228265). This variant has been identified in 41/282548 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing. However, available evidence is insufficient to rule out the pathogenicity of this variant conclusively. 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.
Lildballe Lab, Aarhus University Hospital	RCV004773133	SCV005200538	likely pathogenic	Atrial fibrillation	2024-03-01	criteria provided, single submitter	research	PP2(sup), PM5(m) PP3(sup), BS2 (sup)