ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.51C>G (p.Thr17=) (rs144338227)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181750 SCV000234053 benign not specified 2013-01-17 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725132 SCV000334351 uncertain significance not provided 2015-08-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001095173 SCV000467534 uncertain significance Long QT syndrome 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000268629 SCV000555908 benign Long QT syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622136 SCV000736072 likely benign Cardiovascular phenotype 2016-01-21 criteria provided, single submitter clinical testing
Color RCV000771178 SCV000903111 likely benign Arrhythmia 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000181750 SCV001364011 benign not specified 2019-10-29 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.51C>G results 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 0.00061 in 240046 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12 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 Non-Finnish European origin. c.51C>G has been reported in the literature in individuals affected with Arrhythmia (Berge_2008). This report does not provide an unequivocal conclusion about association of the variant with Arrhythmia (Berge_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cite the variant twice as uncertain significance, twice as likely benign and once as benign. Based on the evidence outlined above, the variant was classified as benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000181750 SCV001433188 likely benign not specified 2020-05-30 criteria provided, single submitter clinical testing

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