chr14-62950522-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_139318.5(KCNH5):c.980G>A(p.Arg327His) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_139318.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH5 | NM_139318.5 | c.980G>A | p.Arg327His | missense_variant | Exon 7 of 11 | ENST00000322893.12 | NP_647479.2 | |
KCNH5 | NM_172375.3 | c.980G>A | p.Arg327His | missense_variant | Exon 7 of 10 | NP_758963.1 | ||
KCNH5 | XM_047431275.1 | c.980G>A | p.Arg327His | missense_variant | Exon 7 of 10 | XP_047287231.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH5 | ENST00000322893.12 | c.980G>A | p.Arg327His | missense_variant | Exon 7 of 11 | 1 | NM_139318.5 | ENSP00000321427.7 | ||
KCNH5 | ENST00000420622.6 | c.980G>A | p.Arg327His | missense_variant | Exon 7 of 10 | 1 | ENSP00000395439.2 | |||
KCNH5 | ENST00000394964.3 | n.1145G>A | non_coding_transcript_exon_variant | Exon 7 of 7 | 1 | |||||
KCNH5 | ENST00000394968.2 | c.806G>A | p.Arg269His | missense_variant | Exon 7 of 11 | 2 | ENSP00000378419.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1450796Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 721842
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy 112 Pathogenic:2
Criteria applied: PS2_VSTR,PS4,PM2,PM5,PP3 -
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Gain of function is likely a mechanism of disease; patch clamp assays have demonstrated a recurring missense variant destabilises the closed channel state, instead favouring channel opening (PMID: 24133262). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Severity of the associated condition has been reported as highly variable and dependent on the variant location (PMID: 36307226). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 2 heterozygotes, 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) 0600 - Variant is located in the annotated ion transport protein domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in over ten individuals including eight where the variant was shown to be de novo (ClinVar, PMID: 36307226). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Inborn genetic diseases Pathogenic:1
The c.980G>A (p.R327H) alteration is located in exon 7 (coding exon 7) of the KCNH5 gene. This alteration results from a G to A substitution at nucleotide position 980, causing the arginine (R) at amino acid position 327 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with KCNH5-related neurodevelopmental disorder and was reported to be the result of a de novo mutation in several of these individuals (Veeramah, 2013; Truty, 2019; Minardi, 2020; Hu, 2022; Happ, 2023). This amino acid position is highly conserved in available vertebrate species. Structural modeling and voltage-clamp analysis demonstrated the critical role of the Arg327 residue in stabilizing the closed-state of the voltage-gated potassium channel Kv10.2 (Yang, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 327 of the KCNH5 protein (p.Arg327His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy and autistic features (PMID: 23647072). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 100784). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNH5 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNH5 function (PMID: 24133262). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); 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: 24133262, 28007376, 32725632, Happ2022[pre-print], 23647072, 35874597) -
Developmental and epileptic encephalopathy, 12 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at