Submissions for variant NM_000238.4(KCNH2):c.3111C>T (p.Asp1037=)

gnomAD frequency: 0.00134  dbSNP: rs200799870

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000712077	SCV000225760	uncertain significance	not provided	2015-01-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000225708	SCV000234044	benign	not specified	2014-08-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001084933	SCV000283982	likely benign	Long QT syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622008	SCV000737984	likely benign	Cardiovascular phenotype	2017-04-26	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.
Athena Diagnostics	RCV000712077	SCV000842492	benign	not provided	2018-03-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000225708	SCV000917557	benign	not specified	2018-07-16	criteria provided, single submitter	clinical testing	Variant summary: KCNH2 c.3111C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00036 in 170308 control chromosomes, predominantly within the African subpopulation at a frequency of 0.004 in the gnomAD database, including 1 homozygote. The observed variant frequency within African control individuals in the gnomAD database is approximately 40 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. To our knowledge, no occurrence of c.3111C>T in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (two classifying the variant as "Likely benign", and one as a VUS). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV001842788	SCV001341832	benign	Cardiac arrhythmia	2018-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001084933	SCV004835856	benign	Long QT syndrome	2024-02-05	criteria provided, single submitter	clinical testing