Submissions for variant NM_172057.2(KCNH2):c.1790G>A (p.Ser597Asn) (rs199473540)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181897	SCV000234200	uncertain significance	not provided	2015-10-22	criteria provided, single submitter	clinical testing	p.Ser937Asn (AGC>AAC): c.2810 G>A in exon 12 of the KCNH2 gene (NM_000238.2)The S937N mutation in the KCNH2 gene has been reported previously in one patient with LQTS and was absent from >2600 reference alleles (Kapplinger JD et al., 2009). Similarly, the S937N mutation was not observed in approximately 5,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other missense mutations affecting neighboring residues (G925R, R948S, R948C, R948H) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein. Although S937N is a conservative replacement of a neutral, polar residue (Ser) with another (Asn), it occurs in a region of the protein conserved in mammalian evolution.In summary, S937N in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Invitae	RCV000631729	SCV000752817	uncertain significance	Long QT syndrome	2017-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine with asparagine at codon 937 of the KCNH2 protein (p.Ser937Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals refered for long QT testing (PMID: 19716085, 23631430).   ClinVar contains an entry for this variant (Variation ID: 67440). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust	RCV000058166	SCV000089686	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.