ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.916G>T (p.Gly306Trp) (rs199472884)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182020 SCV000234323 likely pathogenic not provided 2016-06-10 criteria provided, single submitter clinical testing The G306W variant in the KCNH2 gene has been reported in at least one individual with LQTS and has not been observed in >1000 control alleles (Tester D et al., 2005; Kapa et al., 2009; Giudicessi et al., 2012). Of note, coverage of this nucleotide position in these control alleles was not reported, and presence or absence in the NHLBI Exome Sequencing Project was unable to be determined due to inadequate coverage (1X). This variant was also seen co-segregating with LQTS in four relatives referred for genetic testing at GeneDx. Additionally, G306W is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The Guanine nucleotide at position c.916 is the 3'-terminal nucleotide of exon 4, and two out of three splicing algorithms suggest that this nucleotide substitution either damages or destroys the canonical splice donor site at this exon/intron junction. Other missense variants in KCNH2 that are predicted to affect splicing have been reported in the Human Genome Database (HGMD) in association with LQTS (Stenson et al., 2014). Lastly, a variant at the same residue (G306R) has also been reported in HGMD in association with LQTS. Therefore, G306W is a strong candidate to be pathogenic. Nevertheless, additional segregation and functional studies are necessary to clarify the role of this variant in disease.
Invitae RCV000229643 SCV000283989 likely pathogenic Long QT syndrome 2017-12-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with tryptophan at codon 306 of the KCNH2 protein (p.Gly306Trp). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and tryptophan. It also falls at the last nucleotide of exon 4 of the KCNH2 coding sequence. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with longQT syndrome (PMID: 15840476, 19038855). 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. A different missense substitution at this codon (p.Gly306Arg) is reported to be deleterious (PMID: 18752142). This indicates that the glycine residue is important for KCNH2 protein function. For these reasons, this variant has been classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058273 SCV000089793 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:15840476;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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