ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.568G>A (p.Ala190Thr) (rs150817714)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532958 SCV000627494 uncertain significance Long QT syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 190 of the KCNH2 protein (p.Ala190Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in several individuals affected with sudden infant death syndrome (PMID: 29752375). ClinVar contains an entry for this variant (Variation ID: 67512). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant identified in the KCNH2 gene is located in the cytoplasmic N-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. It is unclear how this variant impacts the function of this protein. 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 1; Long QT syndrome 2 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
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).

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