7-150947011-G-C

Variant names:

• chr7-150947011-G-C
• rs199473027
• NM_000238.4:c.3196C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000238.4(KCNH2):​c.3196C>G​(p.Leu1066Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 3.74

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.3196C>G	p.Leu1066Val	missense_variant	Exon 14 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.3196C>G	p.Leu1066Val	missense_variant	Exon 14 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.2176C>G	p.Leu726Val	missense_variant	Exon 10 of 11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.4029C>G		non_coding_transcript_exon_variant	Exon 12 of 13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Jun 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 67479). This missense change has been observed in individual(s) with long QT syndrome (PMID: 22949429). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1066 of the KCNH2 protein (p.Leu1066Val). -

Congenital long QT syndrome Other:1

-

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

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085;PMID:19841300). 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	Benign	0.15
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.9	.;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.4	N;N
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.045	D;D
Polyphen		1.0	D;D
Vest4		0.46
MutPred		0.73		.;Gain of MoRF binding (P = 0.0818);
MVP		0.91
MPC		0.63
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.48
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.78		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199473027; hg19: chr7-150644099;