ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1888G>A (p.Val630Ile) (rs199472958)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208259 SCV000263978 likely pathogenic Long QT syndrome 2 2015-03-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781487 SCV000919554 likely pathogenic Long QT syndrome 2018-10-25 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.1888G>A (p.Val630Ile) results in a conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 277200 control chromosomes (gnomAD). The variant, c.1888G>A, has been reported in the literature in individuals affected with sudden arrhythmic death syndrome and long QT syndrome (Lahrouchi_2017, Owen_2018). These data indicate that the variant may be associated with disease. In addition, other missense changes affecting the same codon, p.V630A and p.V630L, and nearby p.N629S, p.N629K, p.N629I, p.N629D, and p.S631A, have been reported in affected individuals suggesting this region could be important for KCNH2 protein function. 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) cite the variant as likely pathogenic. Therefore, based on the variant fulfilling the following ACMG criterias: PM1,PM5,PP3, and PP5, the variant was classified as likely pathogenic.
Invitae RCV000781487 SCV001400343 uncertain significance Long QT syndrome 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 630 of the KCNH2 protein (p.Val630Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs199472958, ExAC 0.006%). This variant has been observed in an individual affected with sudden cardiac death (PMID: 28449774). ClinVar contains an entry for this variant (Variation ID: 222669). This variant has been reported not to substantially affect KCNH2 protein function (PMID:8799887). This variant disrupts the p.Val630 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9693036, 16432067, 23303164). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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