ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.211G>C (p.Gly71Arg) (rs199473420)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181935 SCV000234238 pathogenic not provided 2012-12-05 criteria provided, single submitter clinical testing Gly71Arg has been reported previously in two unrelated patients referred for LQTS testing and itwas absent in 800 reference alleles (Napolitano C et al., 2005; Itoh H et al., 2010). Additionally, the NHLBI ESP Exome Variant Server reports Gly71Arg was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Gly71Arg leads to a non-conservative replacement of a non-polar small Glycine residue with a large polar Arginine residue in the N-terminus of the protein. In addition, other missense mutations affecting neighboring codons (Leu69Pro, His70Arg, His70Asn, Pro72Gln, Pro72Leu) have been reported in association with LQTS, supporting the functional importance of this region of the protein. The variant is found in LQT panel(s).
Integrated Genetics/Laboratory Corporation of America RCV001194446 SCV001364009 pathogenic Long QT syndrome 2019-02-11 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.211G>C (p.Gly71Arg) results in a non-conservative amino acid change located in the PAS domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 225120 control chromosomes (gnomAD). c.211G>C causes the same amino acid change (i.e. p.Gly71Arg) as variant c.211G>A. p.Gly71Arg has been reported in the literature (either linked to c.211G>C or c.211G>A or not specified) in individuals affected with Long QT Syndrome (Itoh_2016, Lieve_2013, Mullally_2013, Raju_2013, Itoh_2010, Napolitano_2005). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to result in deficient protein trafficking to the cell membrane, which is suggested to be the dominant mechanism associated with type 2 Long QT syndrome. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058086 SCV000089606 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:16414944). 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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