rs876661348
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4
The NM_000238.4(KCNH2):c.1805T>C(p.Leu602Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L602L) has been classified as Likely benign.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1805T>C | p.Leu602Pro | missense_variant | 7/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.1805T>C | p.Leu602Pro | missense_variant | 7/15 | 1 | NM_000238.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Long QT syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 602 of the KCNH2 protein (p.Leu602Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 26066609; Invitae). ClinVar contains an entry for this variant (Variation ID: 234996). 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 tolerated. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Dec 31, 2013 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Leu602Pro Based on the evidence reviewed below, we classify this variant as a variant of uncertain significance (VUS). The Leu602Pro variant in the KCNH2 gene is novel, and has not been previously reported as a disease-causing mutation nor as a benign polymorphism to our knowledge (after searches of PubMed and Google). Variation at several nearby residues has been associated with LQT2: I593R, I593T, I593G, I593X, P596L, P596R, G601S, G604S, D609N, D609H, D609G, Y611H, Y611X, V612L (UniProtKB; IRCCS Fondazione Salvatore Maugeri database). This is a conservative amino acid change, resulting in the replacement of a nonpolar leucine with a nonpolar proline. The leucine at this location varies in 9 of 32 mammalian species sequenced, and proline is the normal amino acid in stickleback fish. The adjacent residues similarly vary across species. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “benign”. In total the variant has not been seen in >5330 individuals from publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals. There is no variation at this codon listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org/index.htm), as of May 13, 2012. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 12, 2019 | Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 234996; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26066609, 19841300) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 19, 2024 | The p.L602P variant (also known as c.1805T>C), located in coding exon 7 of the KCNH2 gene, results from a T to C substitution at nucleotide position 1805. The leucine at codon 602 is replaced by proline, an amino acid with similar properties, and is located in the transmembrane-spanning S5/pore region. This alteration has been detected in an individual reported to have QT syndrome (LQTS); however, clinical details were limited (Steffensen AB et al. Sci Rep. 2015;5:10009). This amino acid position is not well conserved in available vertebrate species, and proline is the reference amino acid in other 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at