ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.1128+1810C>T

gnomAD frequency: 0.00002  dbSNP: rs972201049
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431050 SCV000515929 uncertain significance not provided 2020-05-27 criteria provided, single submitter clinical testing Located in an alternate transcript of the KCNH2 gene which encodes the hERG-1b isoform; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 379235; Landrum et al., 2016); In silico analysis supports that this variant does not alter protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Published functional studies suggest this variant may affect protein expression of the hERG-1b isoform (Sale et al., 2008), although additional studies are required to further explore its impact on channel function; This variant is associated with the following publications: (PMID: 18776039, 20224422, 32231684)
Fulgent Genetics, Fulgent Genetics RCV000763172 SCV000893761 likely pathogenic Short QT syndrome type 1; Long QT syndrome 2 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001048076 SCV001212065 likely benign Long QT syndrome 2022-08-23 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001841309 SCV001345574 likely benign Cardiac arrhythmia 2019-09-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV002446661 SCV002753910 uncertain significance Cardiovascular phenotype 2020-01-27 criteria provided, single submitter clinical testing The c.1128+1810C>T intronic variant results from a C to T substitution 1810 nucleotides after coding exon 5 in the KCNH2 gene. This alteration has been reported (as NM_172057.2 c.23C>T p.A8V) in an individual with borderline prolonged QTc who suffered excercise-associated sudden cardiac arrest (Sale H et al. Circ. Res., 2008 Sep;103:e81-95). Functional studies suggested that this alteration may impact protein function of an alternate isoform; however, the clinical relevance of that isoform has not been clearly established (Sale H et al. Circ. Res., 2008 Sep;103:e81-95). This nucleotide position is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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