7-150974931-G-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000238.4(KCNH2):c.87C>A(p.Phe29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.87C>A | p.Phe29Leu | missense_variant | Exon 2 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome AF: 6.89e-7 AC: 1AN: 1452354Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 722062
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Long QT syndrome Pathogenic:2
This sequence change replaces phenylalanine with leucine at codon 29 of the KCNH2 protein (p.Phe29Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect KCNH2 protein function (PMID: 26403377, 22396785, 25417810, 21536673, 23721480, 10187793, 30988392). This variant has been observed in several individuals with long QT syndrome (LQTS) and observed to segregate with LQTS in a family (PMID: 17088455, 26403377). ClinVar contains an entry for this variant (Variation ID: 67538). -
The c.87C>A (p.Phe29Leu) variant in KCNH2 gene, that encodes for potassium voltage-gated channel subfamily H member 2, has been identified in multiple unrelated probands (>10) with Long QT syndrome (PMID: 26403377, 29343803, 28235848, 32893267). This variant has been identified as a founder variant in thirty-three members of five apparently unrelated Danish families with congenital long QT syndrome (PMID:26403377). This variant has also been reported in one individual with sudden cardiac death (PMID: 31729605). Several functional studies using transfected HEK cells and Xenopus laevis oocytes revealed a loss-of-function phenotype with trafficking defects, accelerated deactivation of functional channels, altered channel gating, reduced steady-state inactivation current density and a positive voltage shift in inactivation, compared to wild type (PMID: 26403377, 10187793, 21536673, 31557540, 30988392, 22396785). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.843). This variant is absent in the general population database, gnomAD and interpreted as pathogenic in ClinVar (ClinVar ID: 67538). Therefore, the c.87C>A (p.Phe29Leu) variant in the KCNH2 gene is classified as pathogenic. -
Congenital long QT syndrome Other:1
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10187793;PMID:10973849;PMID:11668638;PMID:11854117;PMID:15840476;PMID:15851171;PMID:16937190;PMID:19716085;PMID:21536673;PMID:22396785). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at