ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.916G>C (p.Gly306Arg) (rs199472884)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198797 SCV000253680 likely pathogenic Long QT syndrome 2017-11-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 306 of the KCNH2 protein (p.Gly306Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in two unrelated individuals with long QT syndrome (PMID: 18752142). In addition, a G>T change at this position has also been reported in an individual diagnosed with long QT syndrome (PMID: 15840476). ClinVar contains an entry for this variant (Variation ID: 67543). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Nucleotide substitutions at last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function and splicing. It is is absent from population databases, affects the last nucleotide of the exon, and has been observed in several unrelated individuals with long QT syndrome. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058272 SCV000089792 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:18752142). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Blueprint Genetics RCV000157261 SCV000206991 pathogenic Long QT syndrome 2 2014-08-15 no assertion criteria provided clinical testing

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