chr7-150948446-T-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_000238.4(KCNH2):c.2690A>T(p.Lys897Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000305 in 982,178 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. K897T) has been classified as Benign.
Frequency
Consequence
NM_000238.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2690A>T | p.Lys897Met | missense_variant, splice_region_variant | 11/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2690A>T | p.Lys897Met | missense_variant, splice_region_variant | 11/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000330883.9 | c.1670A>T | p.Lys557Met | missense_variant, splice_region_variant | 7/11 | 1 | |||
KCNH2 | ENST00000684241.1 | n.3523A>T | splice_region_variant, non_coding_transcript_exon_variant | 9/13 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 116930Hom.: 0 Cov.: 27 FAILED QC
GnomAD4 exome AF: 0.00000305 AC: 3AN: 982178Hom.: 0 Cov.: 28 AF XY: 0.00000602 AC XY: 3AN XY: 498550
GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 116938Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 56512
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 23, 2023 | Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces lysine with methioin at codon 897 of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 09, 2022 | 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: "Benign"; Align-GVGD: "Class C0"). 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. ClinVar contains an entry for this variant (Variation ID: 200480). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 897 of the KCNH2 protein (p.Lys897Met). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 04, 2017 | p.Lys897Met (AAG>ATG): c.2690 A>T in exon 11 of the KCNH2 (aka HERG) gene (NM_000238.2). The Lys897Met variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Lys897Met results in a non-conservative amino acid substitution of a positively charged Lysine with a non-polar Methionine at a position that is conserved across species. Mutations in nearby codons (Arg894Cys, Arg894Leu, Gly903Arg) have been reported in association with LQTS, supporting the functional importance of this region of the protein. Also, the NHLBI ESP Exome Variant Server reports Lys897Met was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, another missense change at this codon (Lys897Thr) has been reported as a polymorphism. With the clinical and molecular information available at this time, we cannot definitively determine if Lys897Met is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 16, 2023 | This missense variant replaces lysine with methionine at codon 897 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNH2-related disorders in the literature. This variant has not been identified 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at