chr1-210804149-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_172362.3(KCNH1):c.1480A>G(p.Ile494Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. I494T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KCNH1
NM_172362.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.01

Publications

13 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr1-210804148-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1690786.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

PP5

Variant 1-210804149-T-C is Pathogenic according to our data. Variant chr1-210804149-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 162520.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.1480A>G	p.Ile494Val	missense_variant	Exon 8 of 11	ENST00000271751.10	NP_758872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH1	ENST00000271751.10 link	c.1480A>G	p.Ile494Val	missense_variant	Exon 8 of 11	2	NM_172362.3	ENSP00000271751.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Zimmermann-Laband syndrome 1

Pathogenic:2

Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:not provided

- -

Jun 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Pathogenic:1

Aug 04, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Apr 20, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Temple-Baraitser syndrome

Pathogenic:1

Jan 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;.;D;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;.;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.82

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.8

.;.;L;.;.

PhyloP100

6.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.94

N;.;N;.;.

REVEL

Pathogenic

0.88

Sift

Benign

0.093

T;.;T;.;.

Sift4G

Benign

0.20

T;.;T;.;.

Polyphen

0.99

.;.;D;.;.

Vest4

0.72

MutPred

0.66

.;Loss of catalytic residue at T499 (P = 0.3697);Loss of catalytic residue at T499 (P = 0.3697);.;.;

MVP

0.98

MPC

2.4

ClinPred

0.97

GERP RS

4.5

Varity_R

0.28

gMVP

0.88

Mutation Taster

=68/32

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