7-150947875-G-T

Variant names:

• chr7-150947875-G-T
• rs1480554629
• NM_000238.4:c.2696C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000238.4(KCNH2):​c.2696C>A​(p.Thr899Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000261 in 1,530,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign 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. T899S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.301
• Publications: 0 publications found

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]

KCNH2 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 31 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15988612).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.2696C>A	p.Thr899Lys	missense	Exon 12 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.2408C>A	p.Thr803Lys	missense	Exon 10 of 13	NP_001393682.1
	KCNH2	NM_172057.3		c.1676C>A	p.Thr559Lys	missense	Exon 8 of 11	NP_742054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2696C>A	p.Thr899Lys	missense	Exon 12 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.1676C>A	p.Thr559Lys	missense	Exon 8 of 11	ENSP00000328531.4
	KCNH2	ENST00000713710.1		c.2630C>A	p.Thr877Lys	missense	Exon 12 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1378090 Hom.: 0 Cov.: 36 AF XY: 0.00000147 AC XY: 1 AN XY: 679802

African (AFR) AF: 0.0000318 AC: 1 AN: 31422

American (AMR) AF: 0.00 AC: 0 AN: 35228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24900

East Asian (EAS) AF: 0.00 AC: 0 AN: 35628

South Asian (SAS) AF: 0.00 AC: 0 AN: 78568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4062

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076578

Other (OTH) AF: 0.00 AC: 0 AN: 57490

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.0000482 AC: 2 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Mar 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1006883). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 899 of the KCNH2 protein (p.Thr899Lys).

Cardiovascular phenotype Uncertain:1

Aug 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T899K variant (also known as c.2696C>A), located in coding exon 12 of the KCNH2 gene, results from a C to A substitution at nucleotide position 2696. The threonine at codon 899 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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

Sep 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiac arrhythmia Uncertain:1

Feb 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with lysine at codon 899 of the KCNH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNH2-related disorders in the literature. This variant has not been identified 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostArm	Benign	0.0000033
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.34	N
PhyloP100		0.30
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.35
Sift	Benign	0.48	T
Sift4G	Benign	0.90	T
Polyphen		0.0020	B
Vest4		0.24
MutPred		0.33		Gain of ubiquitination at T899 (P = 0.0011)
MVP		0.65
MPC		0.21
ClinPred		0.075	T
GERP RS		3.0
Varity_R		0.064
gMVP		0.71
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1480554629; hg19: chr7-150644963;