rs786205422

Variant names:

• chr7-150945451-G-C
• rs786205422
• NM_000238.4:c.3394C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000238.4(KCNH2):​c.3394C>G​(p.Pro1132Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000016 in 1,563,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 2.19

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_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27354348).
• BS2: High AC in GnomAdExome4 at 23 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.3394C>G	p.Pro1132Ala	missense_variant	Exon 15 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.3394C>G	p.Pro1132Ala	missense_variant	Exon 15 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.2374C>G	p.Pro792Ala	missense_variant	Exon 11 of 11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.4227C>G		non_coding_transcript_exon_variant	Exon 13 of 13

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000181 AC: 3 AN: 165828 Hom.: 0 AF XY: 0.0000112 AC XY: 1 AN XY: 88896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000381

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000798

Gnomad SAS exome AF: 0.0000424

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000163 AC: 23 AN: 1411616 Hom.: 0 Cov.: 31 AF XY: 0.0000100 AC XY: 7 AN XY: 697548

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000266

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000109

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.21e-7

Gnomad4 OTH exome AF: 0.000291

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:2

Sep 23, 2024

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 proline with alanine at codon 1132 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental functional study has shown that this variant has no impact on channel function (PMID: 34930020). This variant has been reported in an individual affected with long-QT syndrome who also carried a pathogenic missense variant in the KCNQ1 gene (PMID: 23631430). It has also been reported in an individual suspected to be affected with coronary artery disease (PMID: 23861362) and in three individuals with no known arrhythmia phenotypes or other indications for cardiac genetic screening (PMID: 34930020). This variant has been identified in 3/165828 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. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1132 of the KCNH2 protein (p.Pro1132Ala). This variant is present in population databases (rs786205422, gnomAD 0.009%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 23631430, 23861362). ClinVar contains an entry for this variant (Variation ID: 191469). 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. 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. -

not specified Uncertain:1

Nov 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNH2 c.3394C>G (p.Pro1132Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 165828 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3394C>G has been reported in the literature in individuals affected with Long QT syndrome without strong evidence of causality (Lieve_2013), and one individual had a co-occurring variant that some ClinVar submitters classified as pathogenic/likely pathogenic. This report does not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23631430, 23861362, 31696929). ClinVar contains an entry for this variant (Variation ID: 191469). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiovascular phenotype Uncertain:1

Apr 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P1132A variant (also known as c.3394C>G), located in coding exon 15 of the KCNH2 gene, results from a C to G substitution at nucleotide position 3394. The proline at codon 1132 is replaced by alanine, an amino acid with highly similar properties, and is located in the C-terminal region of the protein. This variant was reported to co-occur with a KCNQ1 variant in an individual with mean QTc interval of 500ms and has been reported in an arrhythmia cohort (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Li X et al. Ann Hum Genet, 2020 03;84:161-168). This alteration has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Aug 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia Uncertain:1

May 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with alanine at codon 1132 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental functional study has shown that this variant has no impact on channel function (PMID: 34930020). This variant has been reported in an individual affected with long-QT syndrome who also carried a pathogenic missense variant in the KCNQ1 gene (PMID: 23631430). It has also been reported in an individual suspected to be affected with coronary artery disease (PMID: 23861362) and in three individuals with no known arrhythmia phenotypes or other indications for cardiac genetic screening (PMID: 34930020). This variant has been identified in 3/165828 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;T
Eigen	Benign	-0.033
Eigen_PC	Benign	-0.0056
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.69	T;T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.5	.;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.048	D;T
Polyphen		0.52	P;P
Vest4		0.33
MutPred		0.17		.;Loss of glycosylation at P1132 (P = 0.0372);
MVP		0.64
MPC		0.23
ClinPred		0.076	T
GERP RS		4.2
Varity_R		0.068
gMVP		0.26

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: rs786205422; hg19: chr7-150642539;