rs730882175

chr1-210804143-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_172362.3(KCNH1):c.1486G>A(p.Gly496Arg) 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. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH1 NM_172362.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.62

Genes affected

KCNH1 (HGNC:6250): (potassium voltage-gated channel subfamily H member 1) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_172362.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNH1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 1-210804143-C-T is Pathogenic according to our data. Variant chr1-210804143-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-210804143-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH1	NM_172362.3	c.1486G>A	p.Gly496Arg	missense_variant	8/11	ENST00000271751.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH1	ENST00000271751.10	c.1486G>A	p.Gly496Arg	missense_variant	8/11	2	NM_172362.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460860 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726652

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Zimmermann-Laband syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 16, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -
Pathogenic, no assertion criteria provided	not provided	Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 06, 2022	_x000D_ Criteria applied: PS2, PS3, PS4_MOD, PM2_SUP, PP2, PP3 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 16, 2023	ClinVar contains an entry for this variant (Variation ID: 183418). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 KCNH1 protein function. This variant is also known as NM_002238.3 c.1405G>A, p.Gly469Arg . This missense change has been observed in individual(s) with Zimmermann-Laband syndrome (PMID: 25915598, 33619735). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 496 of the KCNH1 protein (p.Gly496Arg). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2021	Functional studies demonstrate that the G496R variant results in a gain of function effect (Kortum et al., 2015); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26264464, 33594261, 25915598, 26818738, 33811134) -

Temple-Baraitser syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 17, 2023	Criteria applied: PS4,PS2_MOD,PM5,PM2_SUP,PP2,PP3 -
Pathogenic, criteria provided, single submitter	research	Laboratory of Medical Genetics, University of Torino	Nov 29, 2022	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2016

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PP5_very strong;PM1_moderate;PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting -

Temple-Baraitser syndrome;C4551773:Zimmermann-Laband syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;.;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.1	D;.;D;.;.
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D;.;D;.;.
Sift4G	Pathogenic	0.0010	D;.;D;.;.
Polyphen		1.0	.;.;D;.;.
Vest4		0.97
MutPred		0.91		.;Gain of catalytic residue at G496 (P = 0.0329);Gain of catalytic residue at G496 (P = 0.0329);.;.;
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882175; hg19: chr1-210977485; COSMIC: COSV55098016;