rs199472871
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000238.4(KCNH2):c.722C>T(p.Pro241Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000316 in 1,266,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P241S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.722C>T | p.Pro241Leu | missense_variant | 4/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.722C>T | p.Pro241Leu | missense_variant | 4/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000532957.5 | n.945C>T | non_coding_transcript_exon_variant | 4/9 | 2 | ||||
KCNH2 | ENST00000684241.1 | n.1555C>T | non_coding_transcript_exon_variant | 2/13 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000316 AC: 4AN: 1266136Hom.: 0 Cov.: 31 AF XY: 0.00000322 AC XY: 2AN XY: 622080
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 18, 2023 | The p.P241L variant (also known as c.722C>T), located in coding exon 4 of the KCNH2 gene, results from a C to T substitution at nucleotide position 722. The proline at codon 241 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in long QT syndrome cohorts (Shimizu W et al. J Am Coll Cardiol, 2009 Nov;54:2052-62; Walsh R et al. Genet Med, 2021 Jan;23:47-58). Limited functional studies have demonstrated membrane expression that is similar to wild-type levels (Perry MD et al. J Physiol, 2016 Jul;594:4031-49; Mattivi CL et al. Heart Rhythm, 2020 Feb;17:315-323). This amino acid position is well 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. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19926013). 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