7-150950206-A-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000238.4(KCNH2):c.2360T>A(p.Ile787Asn) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I787F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2360T>A | p.Ile787Asn | missense_variant | 9/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2360T>A | p.Ile787Asn | missense_variant | 9/15 | 1 | NM_000238.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome Cov.: 39
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2013 | The Ile787Asn variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ile787Asn results in a semi-conservative amino acid substitution of a non-polar Isoleucine with a polar Asparagine at a position that is well conserved across species. Consequently, in silico analysis predicts Ile787Asn is damaging to the protein structure/function. Mutations in nearby residues (Arg784Trp, Gly785Ala, Glu788Asp, Arg791Trp) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. Furthermore, the Ile787Asn variant 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, Ile787Asn in the KCNH2 gene is a good candidate for a disease-causing mutation. The variant is found in LQT panel(s). - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 31, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 200428). This missense change has been observed in individual(s) with clinical features of long QT syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 787 of the KCNH2 protein (p.Ile787Asn). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at