Submissions for variant NM_000238.4(KCNH2):c.568G>A (p.Ala190Thr)

gnomAD frequency: 0.00076  dbSNP: rs150817714

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000532958	SCV000627494	uncertain significance	Long QT syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 190 of the KCNH2 protein (p.Ala190Thr). 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. This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 29752375). ClinVar contains an entry for this variant (Variation ID: 67512). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Fulgent Genetics, Fulgent Genetics	RCV000765946	SCV000897367	uncertain significance	Short QT syndrome type 1; Long QT syndrome 2	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780360	SCV000917553	benign	not specified	2018-03-06	criteria provided, single submitter	clinical testing	Variant summary: KCNH2 c.568G>A (p.Ala190Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 0.00085 in 31934 control chromosomes (gnomAD and publication controls). The observed variant frequency within African control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.568G>A, has been reported in the literature in individuals affected with Arrhythmia. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000780360	SCV001433429	likely benign	not specified	2020-03-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345368	SCV002653324	likely benign	Cardiovascular phenotype	2020-08-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
PreventionGenetics, part of Exact Sciences	RCV004549487	SCV004795367	likely benign	KCNH2-related disorder	2019-08-07	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058241	SCV000089761	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:14661677;PMID:19841300).