rs199473032

Variant names:

• chr7-150945498-G-A
• rs199473032
• NM_000238.4:c.3347C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_000238.4(KCNH2):​c.3347C>T​(p.Ala1116Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,558,350 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 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: 0.489

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16010553).
• BS2: High AC in GnomAd4 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.3347C>T	p.Ala1116Val	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.3347C>T	p.Ala1116Val	missense_variant	Exon 15 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.2327C>T	p.Ala776Val	missense_variant	Exon 11 of 11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.4180C>T		non_coding_transcript_exon_variant	Exon 13 of 13

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 5 AN: 151244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000307 AC: 5 AN: 163038 Hom.: 0 AF XY: 0.0000461 AC XY: 4 AN XY: 86776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000785

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 24 AN: 1406988 Hom.: 0 Cov.: 31 AF XY: 0.0000230 AC XY: 16 AN XY: 694664

Gnomad4 AFR exome AF: 0.0000313

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000275

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000185

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome AF: 0.0000396 AC: 6 AN: 151362 Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4 AN XY: 74018

Gnomad4 AFR AF: 0.0000486

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000572 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000859 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:2

Feb 05, 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 alanine with valine at codon 1116 of the KCNH2 protein. Computational prediction tool 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). This variant is found within a highly conserved C-terminus region (a.a. 843-1159). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). This variant has been reported in three individuals affected with long QT syndrome (PMID: 16116052, 32893267), including one who was compound heterozygous with a common polymorphism p.Lys897Thr (PMID:16116052). Relatives who carried this variant p.Ala1116Val alone were asymptomatic. This variant has been reported in an individual affected with sudden infant death (PMID: 29544605). An experimental study has shown that these two variants, when coexpressed in mammalian cells, resulted in reduced current amplitude, compared with coexpression of either allele with the wild type protein (PMID: 16116052). A functional study expressing only the p.Ala1116V variant did not show altered electrophysiological parameters when compared to WT (PMID: 19673885). This variant has been identified in 6/194268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1116 of the KCNH2 protein (p.Ala1116Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 16116052, 23158531, 26220970, 29544605). ClinVar contains an entry for this variant (Variation ID: 67491). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16116052, 23303164). 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 provided Uncertain:1

Aug 08, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with p.(K897T) in trans in one severe, symptomatic LQTS patient, whereas three relatives with p.(A1116V) alone were asymptomatic but exhibited transient mild QTc prolongation (Crotti et al., 2005); of note, p.(K897T) is classified as benign at GeneDx and in ClinVar (ClinVar ID#67427); Identified in one patient with sudden infant death syndrome (SIDS) and one patient with SCN5A-negative Brugada syndrome (Tester et al., 2018; Di Resta et al., 2015); Crotti et al. (2005) showed that co-expressing p.(A1116V) and p.(K897T) affected current density, however, additional functional studies looking at p.(A1116V) showed similar electrophysiological properties as wild type (Crotti et al., 2005; Jou et al., 2013; Mannikko et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23303164, 19673885, 23158531, 21685056, 18808722, 23608144, 18284507, 22338672, 16116052, 25418379, 29544605, 26220970) -

Cardiovascular phenotype Uncertain:1

Feb 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3347C>T (p.A1116V) alteration is located in exon 15 (coding exon 15) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 3347, causing the alanine (A) at amino acid position 1116 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

Nov 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with valine at codon 1116 of the KCNH2 protein. Computational prediction tool 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). This variant is found within a highly conserved C-terminus region (a.a. 843-1159). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). This variant has been reported in three individuals affected with long QT syndrome (PMID: 16116052, 32893267), including one who was compound heterozygous with a common polymorphism p.Lys897Thr (PMID:16116052). Relatives who carried this variant p.Ala1116Val alone were asymptomatic. This variant has been reported in an individual affected with sudden infant death (PMID: 29544605). An experimental study has shown that these two variants, when coexpressed in mammalian cells, resulted in reduced current amplitude, compared with coexpression of either allele with the wild type protein (PMID: 16116052). A functional study expressing only the p.Ala1116V variant did not show altered electrophysiological parameters when compared to WT (PMID: 19673885). This variant has been identified in 6/194268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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:16116052). 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	0.077
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.71	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.69	.;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.19	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.0010	B;B
Vest4		0.28
MVP		1.0
MPC		0.17
ClinPred		0.060	T
GERP RS		0.69
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.031
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199473032; hg19: chr7-150642586;