chr7-150959701-C-T

Variant names:

• chr7-150959701-C-T
• rs150988911
• NM_000238.4:c.343G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PP3_Moderate BS2_Supporting

The NM_000238.4(KCNH2):​c.343G>A​(p.Val115Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 O:1
• Conservation: PhyloP100: 7.37

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.

• PM1: In a domain PAC (size 52) in uniprot entity KCNH2_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_000238.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• BS2: High AC in GnomAdExome4 at 6 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.343G>A	p.Val115Met	missense_variant	Exon 3 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.343G>A	p.Val115Met	missense_variant	Exon 3 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.566G>A		non_coding_transcript_exon_variant	Exon 3 of 9	2
KCNH2	ENST00000684241.1	n.1176G>A		non_coding_transcript_exon_variant	Exon 1 of 13

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251426 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135906

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74464

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:2

Sep 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 tolerated. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 115 of the KCNH2 protein (p.Val115Met). This variant is present in population databases (rs150988911, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome (LQTS) (PMID: 18441445). ClinVar contains an entry for this variant (Variation ID: 67496). Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 25417810, 32475984). 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. -

Jun 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with methionine at codon 115 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Electrophysiological functional studies suggest that this variant may not impact KCNH2 activity (PMID: 25417810); the clinical relevance of this observation is not known. This variant has been reported in an individual affected with long QT syndrome (PMID: 18441445). This variant has been identified in 4/251426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Long QT syndrome 2 Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiovascular phenotype Uncertain:1

May 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V115M variant (also known as c.343G>A), located in coding exon 3 of the KCNH2 gene, results from a G to A substitution at nucleotide position 343. The valine at codon 115 is replaced by methionine, an amino acid with highly similar properties, and is located in the cytoplasmic PAC region. This variant has been detected in long QT syndrome (LQTS) cohorts; however, details were limited and one reported case carried a second variant in a LQTS-related gene (Nagaoka I et al. Circ J, 2008 May;72:694-9; Jiménez-Jáimez J et al. Rev Esp Cardiol (Engl Ed), 2017 Oct;70:808-816). This variant has also been detected in exome cohorts (Amendola LM et al. Genome Res, 2015 Mar;25:305-15). In vitro studies by one group indicated that this variant may not adversely impact protein trafficking or channel function compared to wild type (Anderson CL et al. Nat Commun, 2014 Nov;5:5535). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia Uncertain:1

Apr 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with methionine at codon 115 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Electrophysiological functional studies suggest that this variant may not impact KCNH2 activity (PMID: 25417810); the clinical relevance of this observation is not known. This variant has been reported in an individual affected with long QT syndrome (PMID: 18441445). This variant has been identified in 4/251426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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:18441445). 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	0.94
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.2	N;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.47	P;.
Vest4		0.80
MVP		0.97
MPC		1.3
ClinPred		0.71	D
GERP RS		4.7
Varity_R		0.67
gMVP		0.96

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: rs150988911; hg19: chr7-150656789; COSMIC: COSV51129505; COSMIC: COSV51129505;