Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001064914 | SCV001229850 | uncertain significance | Long QT syndrome | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 483 of the KCNH2 protein (p.Val483Ile). This variant is present in population databases (rs755834128, gnomAD 0.005%). This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 31522018, 32145446). This variant is also known as 427G>A V143I. ClinVar contains an entry for this variant (Variation ID: 858924). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
| Color Diagnostics, |
RCV001842607 | SCV001354275 | uncertain significance | Cardiac arrhythmia | 2023-04-03 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with isoleucine at codon 483 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one family, including an individual affected with atrial fibrillation as well as a related individual affected with sudden infant death (PMID: 31522018). This variant has been identified in 7/251452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV003160535 | SCV003864707 | uncertain significance | Cardiovascular phenotype | 2023-02-06 | criteria provided, single submitter | clinical testing | The p.V483I variant (also known as c.1447G>A), located in coding exon 6 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1447. The valine at codon 483 is replaced by isoleucine, an amino acid with highly similar properties. This variant (also referred to as p.V143I, c.427G>A) has been detected in two sudden infant death (SIDS) cases (Santori M et al. Forensic Sci Int Genet, 2019 Nov;43:102159; Liebrechts-Akkerman G et al. Forensic Sci Int Genet, 2020 May;46:102266). A relative of one SIDS case also with this variant had atrial fibrillation, syncope, and left ventricular dilation, while other relatives with this variant were reportedly unaffected (Santori M et al. Forensic Sci Int Genet, 2019 Nov;43:102159). This variant has also been detected in a cohort not selected for the presence of arrhythmia phenotypes; however, cardiovascular details were limited (Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |