rs886041300

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_172362.3(KCNH1):c.1070G>A(p.Arg357Gln) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R357W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KCNH1
NM_172362.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 7.60

Publications

14 publications found

Variant links:

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]

KCNH1 Gene-Disease associations (from GenCC):

KCNH1 associated disorder
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Illumina
Temple-Baraitser syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
Zimmermann-Laband syndrome 1
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Zimmermann-Laband syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KCNH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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, 1 uncertain in NM_172362.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-210920033-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1493344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 1-210920032-C-T is Pathogenic according to our data. Variant chr1-210920032-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 279981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH1	NM_172362.3 link	c.1070G>A	p.Arg357Gln	missense_variant	Exon 7 of 11	ENST00000271751.10	NP_758872.1	O95259-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH1	ENST00000271751.10 link	c.1070G>A	p.Arg357Gln	missense_variant	Exon 7 of 11	2	NM_172362.3	ENSP00000271751.4		O95259-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 13, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32860008, 26818738, 27267311, 28628100, 28867141, 31278258, 32581362, 33594261, 31785789, 33057194, 36801247, 37541188, 37853563, 35982159, 38372889, 26264464) -

Dec 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 279981). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 357 of the KCNH1 protein (p.Arg357Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNH1-related conditions (PMID: 23020937, 26264464, 26818738). In at least one individual the variant was observed to be de novo. 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. For these reasons, this variant has been classified as Pathogenic. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 27, 2020

Laboratoire Génétique Moléculaire, CHRU TOURS

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Zimmermann-Laband syndrome 1

Pathogenic:3

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.R357Q in KCNH1 (NM_172362.3) causes the same amino acid change as a previously established pathogenic variant. This variant has been reported in multiple unrelated individuals as a de novo variant (Fukai R et al,Bramswig NC et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic.The p.R357Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.R357Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 357 of KCNH1 is conserved in all mammalian species. The nucleotide c.1070 in KCNH1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 23, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

_x000D_ Criteria applied: PS2_VSTR, PS4, PM5, PM2_SUP, PP2, PP3 -

Temple-Baraitser syndrome

Pathogenic:3

Jan 03, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant has been previously reported as de novo in a similarly affected individual (PMID: 26818738, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279981, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.872, 3CNET: 0.808, PP3_P). A missense variant is a common mechanism associated with Temple-Baraitser syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KCNH1-related disorder

Pathogenic:2

Apr 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: KCNH1 c.1070G>A (p.Arg357Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250740 control chromosomes. c.1070G>A has been observed in multiple individual(s) affected with Temple-Baraitser and Zimmermann-Laband Syndromes and neurodevelopmental delay/neurodevelopmental comorbidities, inlcuding at-least 4 de novo occurrences (examples, Bramswig_2015, Gripp_2021, Wu_2024). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26264464, 33594261, 38764027). ClinVar contains an entry for this variant (Variation ID: 279981). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 20, 2020

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The KCNH1 c.1070G>A (p.Arg357Gln) variant is a missense variant that has been reported in two studies, in which it is found in a heterozygous, de novo state in five unrelated individuals with KCNH1-related disorders (Bramswig et al. 2015; Fukai et al. 2016). The clinical presentation of the affected individuals includes global developmental delay, epilepsy, neonatal hypotonia, nail aplasia/hypoplasia, broad thumbs or toes, long great toes, and craniofacial dysmorphism. The p.Arg357Gln variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the p.Arg357Gln variant is classified as pathogenic for KCNH1-related disorders. -

Inborn genetic diseases

Pathogenic:1

Apr 22, 2016

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Seizure;C0036857:Intellectual disability, severe;C0424503:Abnormal facial shape

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Intellectual disability

Pathogenic:1

Dec 30, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Seizure

Pathogenic:1

Diagnostic Laboratory, Strasbourg University Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

.;.;D;.;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;.;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

.;.;H;.;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.7

D;.;D;.;.

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0080

D;.;D;.;.

Sift4G

Uncertain

0.016

D;.;D;.;.

Polyphen

1.0

.;.;D;.;.

Vest4

0.93

MutPred

0.77

.;Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);.;.;

MVP

1.0

MPC

2.7

ClinPred

1.0

GERP RS

5.5

Varity_R

0.87

gMVP

0.98

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over