rs199472853

Positions:

• chr7-150974731-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The ENST00000262186.10(KCNH2):​c.287T>C​(p.Ile96Thr) 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I96V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 ENST00000262186.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 9.09

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in ENST00000262186.10
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.287T>C	p.Ile96Thr	missense_variant	2/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.287T>C	p.Ile96Thr	missense_variant	2/15	1	NM_000238.4	ENSP00000262186	P1
KCNH2	ENST00000532957.5	n.510T>C		non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lildballe Lab, Aarhus University Hospital

Mar 01, 2024

PM2(sup), PM1(sup), PP2(sup), PP3(sup) -

Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PP3_Moderate+PS4_Supporting -

Congenital long QT syndrome Other:1

not provided, no classification 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:11468227;PMID:11668638;PMID:16937190). 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	0.84
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.2	D;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0090	D;T
Polyphen		0.30	B;.
Vest4		0.87
MutPred		0.91		Gain of disorder (P = 0.0216);.;
MVP		0.97
MPC		2.4
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.63
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs199472853; hg19: chr7-150671819;