rs1553344875

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_172362.3(KCNH1):c.1705G>A(p.Val569Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V569V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KCNH1
NM_172362.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.62

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-210797718-C-T is Pathogenic according to our data. Variant chr1-210797718-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 520561.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH1	NM_172362.3 link	c.1705G>A	p.Val569Met	missense_variant	Exon 9 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.1705G>A	p.Val569Met	missense_variant	Exon 9 of 11	2	NM_172362.3	ENSP00000271751.4		O95259-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727148

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111904

Other (OTH)

AF:

0.00

AC:

AN:

60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Mar 11, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 26818738, 25915598, 25420144, 25711872, 23424202, 26264464, 9738473, 28330790, 18203178) -

Inborn genetic diseases

Uncertain:1

Feb 01, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1705G>A (p.V569M) alteration is located in exon 9 (coding exon 9) of the KCNH1 gene. This alteration results from a G to A substitution at nucleotide position 1705, causing the valine (V) at amino acid position 569 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. The p.V569M amino acid is located in the cyclic nucleotide-binding domain of the KCNH1 protein. Based on internal structural analysis, p.V569M does not decrease the stability of the protein structure and there are no other pathogenic alterations nearby (Whicher, 2016). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

.;.;D;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D;D;.;D

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.71

D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Benign

0.90

.;.;L;.;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-2.8

D;.;D;.;.

REVEL

Pathogenic

0.72

Sift

Benign

0.13

T;.;T;.;.

Sift4G

Benign

0.31

T;.;T;.;.

Polyphen

0.90

.;.;P;.;.

Vest4

0.62

MutPred

0.37

.;Gain of methylation at K574 (P = 0.1235);Gain of methylation at K574 (P = 0.1235);.;.;

MVP

0.99

MPC

2.1

ClinPred

0.99

GERP RS

5.4

Varity_R

0.36

gMVP

0.69

Mutation Taster

=12/88

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over