rs587777164

Positions:

• chr14-62950522-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000322893.12(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R327C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH5 ENST00000322893.12 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.90

Genes affected

KCNH5 (HGNC:6254): (potassium voltage-gated channel subfamily H member 5) This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a transmembrane_region Helical; Voltage-sensor; Name=Segment S4 (size 20) in uniprot entity KCNH5_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000322893.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-62950523-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1488521.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNH5. . Gene score misZ 2.509 (greater than the threshold 3.09). Trascript score misZ 3.7308 (greater than threshold 3.09). GenCC has associacion of gene with infantile-onset epilepsy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 14-62950522-C-T is Pathogenic according to our data. Variant chr14-62950522-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 100784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-62950522-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.980G>A	p.Arg327His	missense_variant	7/11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.980G>A	p.Arg327His	missense_variant	7/10		NP_758963.1
KCNH5	XM_047431275.1	c.980G>A	p.Arg327His	missense_variant	7/10		XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12	c.980G>A	p.Arg327His	missense_variant	7/11	1	NM_139318.5	ENSP00000321427	P1
KCNH5	ENST00000420622.6	c.980G>A	p.Arg327His	missense_variant	7/10	1		ENSP00000395439
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		ENSP00000378419

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450796 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy 112 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 23, 2024	Criteria applied: PS2_VSTR,PS4,PM2,PM5,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 11, 2024	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

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

Labcorp Genetics (formerly Invitae), Labcorp

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.6	H;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.96
MutPred		0.76		Gain of catalytic residue at K324 (P = 0.0062);Gain of catalytic residue at K324 (P = 0.0062);.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.73
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587777164; hg19: chr14-63417240; COSMIC: COSV59758318;