7-150952720-G-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The ENST00000262186.10(KCNH2):c.1262C>A(p.Thr421Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T421M) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000262186.10 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1262C>A | p.Thr421Lys | missense_variant | 6/15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.1262C>A | p.Thr421Lys | missense_variant | 6/15 | 1 | NM_000238.4 | ENSP00000262186 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 31, 2013 | p.Thr421Lys (ACG>AAG): c.1262 C>A in exon 6 of the KCNH2 (aka HERG) gene (NM_000238.2)While the Thr421Lys mutation in the KCNH2 gene has not been reported to our knowledge, a mutation affecting this same codon, Thr421Met, has been reported in association with LQTS (Tester D et al., 2005). Additionally, mutations in nearby residues (Leu413Pro, Tyr420Cys, Ala422Thr) have been reported in association with LQTS, further supporting the functional importance of this codon and this region of the protein. Thr421Lys results in a semi-conservative amino acid substitution of a neutral, polar Threonine with a positively charged Lysine at a position that is conserved across species. In silico analysis predicts Thr421Lys is probably damaging to the protein structure/function. Furthermore, Thr421Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, Thr421Lys in the KCNH2 gene is interpreted as a likely disease-causing mutation. The variant is found in LQT panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at