7-150974851-C-A
Variant summary
Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_000238.4(KCNH2):c.167G>T(p.Arg56Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,910 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
Publications
- long QT syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- long QT syndrome 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
- short QT syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- short QT syndrome type 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- Brugada syndromeInheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
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ACMG classification
Our verdict: Pathogenic. The variant received 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.167G>T | p.Arg56Leu | missense_variant | Exon 2 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.167G>T | p.Arg56Leu | missense_variant | Exon 2 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000713710.1 | c.167G>T | p.Arg56Leu | missense_variant | Exon 2 of 15 | ENSP00000519013.1 | ||||
KCNH2 | ENST00000532957.5 | n.390G>T | non_coding_transcript_exon_variant | Exon 2 of 9 | 2 | |||||
KCNH2 | ENST00000713700.1 | n.125G>T | non_coding_transcript_exon_variant | Exon 2 of 9 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457910Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 725196 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest the p.(R56L) variant impacts protein trafficking and current density (PMID: 35688148); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22396785, 35688148) -
Long QT syndrome Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 56 of the KCNH2 protein (p.Arg56Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 200557). 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. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 35688148). This variant disrupts the p.Arg56 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 11854117; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at