Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181987 | SCV000234290 | pathogenic | not provided | 2021-02-02 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID#200660; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease |
| Labcorp Genetics |
RCV000631709 | SCV000752796 | pathogenic | Long QT syndrome | 2023-05-11 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 34319147). ClinVar contains an entry for this variant (Variation ID: 200660). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Pro910Argfs*66) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). |
| Ambry Genetics | RCV002426875 | SCV002741541 | pathogenic | Cardiovascular phenotype | 2021-03-24 | criteria provided, single submitter | clinical testing | The c.2724_2728dupGGGGC pathogenic mutation, located in coding exon 12 of the KCNH2 gene, results from a duplication of GGGGC at nucleotide position 2724, causing a translational frameshift with a predicted alternate stop codon (p.P910Rfs*66). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
| Laboratory for Molecular Medicine, |
RCV004017460 | SCV004847330 | likely pathogenic | Congenital long QT syndrome | 2023-09-29 | criteria provided, single submitter | clinical testing | The p.Pro910ArgfsX66 variant in KCNH2 has not been reported in the literature in individuals with KCNH2-associated disorders but has been reported by other clinical laboratories in ClinVar (Variation ID: 200660). It was absent from large population studies (gnomAD v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 910 and leads to a premature termination codon 66 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KCNH2 gene is an established disease mechanism in autosomal dominant long QT syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant long QT syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting. |