rs587777164
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_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. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R327C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_139318.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH5 | NM_139318.5 | c.980G>A | p.Arg327His | missense_variant | 7/11 | ENST00000322893.12 | |
KCNH5 | NM_172375.3 | c.980G>A | p.Arg327His | missense_variant | 7/10 | ||
KCNH5 | XM_047431275.1 | c.980G>A | p.Arg327His | missense_variant | 7/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH5 | ENST00000322893.12 | c.980G>A | p.Arg327His | missense_variant | 7/11 | 1 | NM_139318.5 | P1 | |
KCNH5 | ENST00000420622.6 | c.980G>A | p.Arg327His | missense_variant | 7/10 | 1 | |||
KCNH5 | ENST00000394964.3 | n.1145G>A | non_coding_transcript_exon_variant | 7/7 | 1 | ||||
KCNH5 | ENST00000394968.2 | c.806G>A | p.Arg269His | missense_variant | 7/11 | 2 |
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:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 08, 2023 | Criteria applied: PS2_VSTR, PS4, PM2_SUP, PM5_MOD, PP3 - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 14, 2023 | 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
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 19, 2022 | 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
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 16, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at