rs199472921

chr7-150951712-C-Gchr7-150951712-C-T

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.72

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000238.4
• PM2: Very rare variant; Number of alleles below threshold, Median coverage is 34.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150951712-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 67229. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 7-150951712-C-G is Pathogenic according to our data. Variant chr7-150951712-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 67230. Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-150951712-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1681G>C	p.Ala561Pro	missense_variant	7/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1681G>C	p.Ala561Pro	missense_variant	7/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK:

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2018

The p.A561P pathogenic mutation (also known as c.1681G>C), located in coding exon 7 of the KCNH2 gene, results from a G to C substitution at nucleotide position 1681. The alanine at codon 561 is replaced by proline, an amino acid with highly similar properties. This alteration was detected in a proband with long QT syndrome (LQTS) with drug-induced torsades de pointes as well as in the proband's father and brother, both of whom exhibited prolonged QTc intervals (Bellocq C et al. Mol Pharmacol. 2004;66(5):1093-102). In vitro functional studies have reported that this alteration results in abnormal protein trafficking and altered ion channel function (Bellocq C et al. Mol Pharmacol. 2004;66(5):1093-102; Anderson CL et al. Nat Commun. 2014;5:5535; Jouni M et al. J Am Heart Assoc. 2015;4(9):e002159). Two disease-causing mutations, p.A561V and p.A561T, have been described in the same codon (Curran ME et al. Cell. 1995;80(5):795-803; Dausse E et al. J Mol Cell Cardiol. 1996;28(8):1609-15). In addition, internal structural analysis indicates that this alteration, which occurs in the S5 domain of the central pore, is structurally disruptive (Ambry internal data; Long SB et al. Nature. 2007;450(7168):376-82). Based on the supporting evidence, p.A561P is interpreted as a disease-causing mutation. -

Congenital long QT syndrome Other:1

not provided, no assertion provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15280442;PMID:15159330). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

D

BayesDel_noAF

Pathogenic

0.59

Cadd

Pathogenic

28

Dann

Uncertain

1.0

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.95

D

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

D

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.90

D

PROVEAN

Pathogenic

-4.8

D;D;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.97

MutPred

0.94

.;Loss of stability (P = 0.1365);.;

MVP

1.0

MPC

2.5

ClinPred

1.0

D

GERP RS

4.4

Varity_R

0.99

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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: rs199472921; hg19: chr7-150648800;