7-150952757-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2
The NM_000238.4(KCNH2):c.1225G>A(p.Val409Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,144 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 (★★).
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1225G>A | p.Val409Met | missense_variant | Exon 6 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251470Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135910
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461880Hom.: 0 Cov.: 34 AF XY: 0.0000303 AC XY: 22AN XY: 727248
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74456
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:2
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 409 of the KCNH2 protein (p.Val409Met). This variant is present in population databases (rs539146547, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with KCNH2-related conditions (PMID: 31696929, 32233023, 37589201). ClinVar contains an entry for this variant (Variation ID: 456884). 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 disruptive. 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 valine with methionine at codon 409 of the KCNH2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved pore region (a.a. 404-659). 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 an individual affected with epilepsy (PMID: 31696929) and in an individual affected with sudden infant death (PMID: 37589201). This variant has been identified in 16/251470 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. -
Wolff-Parkinson-White pattern Uncertain:1
This variant was identified in an individual with Wolff-Parkinson-White syndrome -
Long QT syndrome 2 Uncertain:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with long QT syndrome 2 (MIM#613688). Gain of function is also a known mechanism associated with short QT syndrome 1 (MIM#609620) (OMIM, PMID: 10753933; PMID: 21777565). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (16 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional S1 transmembrane domain. The S1 transmembrane domain has been shown to play a role in regulating channel activation and deactivation (PMID: 28280240). (SP) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Alternative missense changes to glutamic acid and leucine have been described as variants of unknown significance in ClinVar and the literature, respectively (PMID: 32383558). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant is present in ClinVar as a VUS. It has also been reported as a VUS in the literature in a patient with epilepsy and in a patient with Wolff-Parkinson-White syndrome (PMID: 31696929, 32233023). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Uncertain:1
Identified in association with epilepsy, sudden infant death syndrome (SIDS), and Wolff-Parkinson-White (WPW) syndrome (PMID: 31696929, 37589201, 32233023); also reported as p.(V69M) due to alternate nomenclature; 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: 32233023, 31696929, 37589201) -
Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1
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Cardiac arrhythmia Uncertain:1
This missense variant replaces valine with methionine at codon 409 of the KCNH2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved pore region (a.a. 404-659). 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 an individual affected with epilepsy (PMID: 31696929) and in an individual affected with sudden infant death (PMID: 37589201). This variant has been identified in 16/251470 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at