NM_000238.4:c.967G>A
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_000238.4(KCNH2):c.967G>A(p.Asp323Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,004 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. D323H) has been classified as Uncertain significance.
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: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.967G>A | p.Asp323Asn | missense_variant | Exon 5 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152242Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 250642 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461762Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727188 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74380 show subpopulations
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:2
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 323 of the KCNH2 protein (p.Asp323Asn). This variant is present in population databases (rs199472887, gnomAD 0.01%). This missense change has been observed in individual(s) with Long QT syndrome (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67551). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
This missense variant replaces aspartic acid with asparagine at codon 323 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant is found within a highly conserved cytoplasmic region (a.a. 1-403). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual suspected long QT syndrome (PMID: 19716085, 26920202). One of these individuals also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (PMID:26920202). This variant has been identified in 7/282048 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Uncertain:1
The c.967G>A (p.D323N) alteration is located in exon 5 (coding exon 5) of the KCNH2 gene. This alteration results from a G to A substitution at nucleotide position 967, causing the aspartic acid (D) at amino acid position 323 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1
- -
Congenital long QT syndrome Other:1
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). 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