ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1496T>G (p.Leu499Arg) (rs794728370)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181793 SCV000234096 pathogenic not provided 2012-02-28 criteria provided, single submitter clinical testing This variant is denoted c.1496 T>G at the cDNA level or p.Leu499Arg (L499R) at the protein level. the T>G nucleotide substitution in exon 6 of the KCNH2 gene, resulting in the replacement of a Leucine codon (CTC) with an Arginine codon (CGC) at amino acid position 499. The Leu499Arg variant in the KCNH2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Leu499Arg is a non-conservative amino acid substitution of a neutral, non-polar Leucine with a positively charged Arginine at a position that is conserved across species. In silico analysis predicts Leu499Arg to be possibly damaging to protein structure or function. Mutations in a nearby codon (Asp501Asn, Asp501Gly, Asp501His) have been reported in association with LQTS, supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports Leu499Arg was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Internal familial studies support that this variant segregates with disease. The variant is found in LQT panel(s).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223922 SCV000280117 uncertain significance not specified 2013-07-29 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Leu499Arg Based on the lack of data available on the variant, we classify it as a variant of unknown significance. The variant is novel. It has not be seen in healthy controls or patients with long QT syndrome. This is a non-conservative amino acid substitution with a neutral, non-polar Leucine replaced by a positively charged Arginine. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The Leucine at codon 499 is highly conserved across species. Other variants at nearby codons have been reported in association with long QT (p.Asp501Asn, p.Asp501Gly, p.Asp501His). In total the variant has not been seen in 6500 publicly available population datasets. There is no variation at codon 499 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of September 13th, 2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of September 13th, 2012).

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