Submissions for variant NM_172056.2(KCNH2):c.775G>A (p.Asp259Asn) (rs199472876)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181767	SCV000234070	uncertain significance	not provided	2016-07-12	criteria provided, single submitter	clinical testing	The D259N variant of uncertain significance in the KCNH2 gene has been reported previously in one individual referred for LQTS genetic testing; however, detailed clinical information and segregation data were not provided (Kapplinger et al., 2009). This variant was absent in 2,600 published control alleles (Kappliner et al., 2009); however, data from other control individuals was not available to assess whether D259N may be a common benign variant in the general population. The D259N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae	RCV000475069	SCV000543418	uncertain significance	Long QT syndrome	2017-03-07	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 259 of the KCNH2 protein (p.Asp259Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. While this variant is present in population databases (rs199472876), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual referred for long QT syndrome testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67527). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and potentially affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust	RCV000058256	SCV000089776	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.