Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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 | 2019-08-12 | 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. 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 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 and their clinical significance is uncertain. 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, |
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. |