rs199473518
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000238.4(KCNH2):c.1693G>T(p.Ala565Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,772 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A565T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1693G>T | p.Ala565Ser | missense_variant | 7/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.1693G>T | p.Ala565Ser | missense_variant | 7/15 | 1 | NM_000238.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461772Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727190
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 20, 2017 | The p.A565S variant (also known as c.1693G>T), located in coding exon 7 of the KCNH2 gene, results from a G to T substitution at nucleotide position 1693. The alanine at codon 565 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a long QT syndrome (LQTS) cohort (Itoh H et al. Eur J Hum Genet. 2016;24:1160-6). Other alterations affecting the same amino acid, p.A565T (c.1693G>A) and p.A565P (c.1693G>C), have also been reported in LQTS cohorts; however, clinical details were not provided (Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Burgos M et al. Mol Diagn Ther. 2016;20(4):353-62). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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