Submissions for variant NM_000238.4(KCNH2):c.211G>C (p.Gly71Arg)

dbSNP: rs199473420

Total submissions: 3

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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.