KCNH2 p.Thr613Met

Variant names:

• chr7-150951555-G-A
• rs199473524
• NM_000238.4:c.1838C>T
• KCNH2 p.Thr613Met

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_SupportingO7_SupportingO8_Supporting

The NM_000238.4(KCNH2):c.1838C>T (p.Thr613Met) variant causes a missense change involving the alteration of a conserved nucleotide. The gene KCNH2 is a known oncogene (CancerMine: 4 oncogene citations). The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,876 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.85). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000280121: This mutation reportedly prevented normal trafficking of the HERG protein to the surface membrane, as shown by the decrease in cell-surface chemiluminescence of HA-tagged mutant subunits compared with HA-tagged WT HERG subunits." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.T613A: Likely_pathogenic (ClinVar VariationId 2049671, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T613P: Uncertain_significance (ClinVar VariationId 4721768, 1 star); p.T613= (synonymous): Likely_benign (ClinVar VariationId 3532338, 1 star); p.T613= (synonymous): Likely_benign (ClinVar VariationId 527061, 2 stars) The variant has been observed in cBioPortal in 3 samples across 3 studies and 2 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 9.85
• Publications: 43 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Genomics England PanelApp, G2P, ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000001, AC = 1 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 18 pathogenic, 0 benign (OR vs. background: 185.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 2.50 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNH2 NM_000238.4	MANE Select	c.1838C>T p.Thr613Met	missense	Exon 7 of 15	Prot: NP_000229.1 UniProt:
	KCNH2 NM_001406753.1		c.1550C>T p.Thr517Met	missense	Exon 5 of 13	Prot: NP_001393682.1 UniProt:
	KCNH2 NM_172056.3		c.1838C>T p.Thr613Met	missense	Exon 7 of 9	Prot: NP_742053.1 UniProt:

KCNH2 NM_000238.4

MANE Select

HGVSc / HGVSpc.1838C>Tp.Thr613Met

Exon rankExon 7 of 15

missense

Prot: NP_000229.1UniProt: Q12809-1

KCNH2 NM_001406753.1

HGVSc / HGVSpc.1550C>Tp.Thr517Met

Exon rankExon 5 of 13

missense

Prot: NP_001393682.1UniProt: Q12809-7

KCNH2 NM_172056.3

HGVSc / HGVSpc.1838C>Tp.Thr613Met

Exon rankExon 7 of 9

missense

Prot: NP_742053.1UniProt: Q12809-5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNH2 ENST00000262186.10	TSL:1MANE Select	c.1838C>T p.Thr613Met	missense	Exon 7 of 15	Prot: ENSP00000262186.5 UniProt:
	KCNH2 ENST00000330883.9	TSL:1	c.818C>T p.Thr273Met	missense	Exon 3 of 11	Prot: ENSP00000328531.4 UniProt:
	KCNH2 ENST00000461280.2	TSL:1	n.1136C>T	non_coding_transcript_exon	Exon 3 of 5	Prot:

KCNH2 ENST00000262186.10

TSL:1MANE Select

HGVSc / HGVSpc.1838C>Tp.Thr613Met

Exon rankExon 7 of 15

missense

Prot: ENSP00000262186.5UniProt: Q12809-1

KCNH2 ENST00000330883.9

TSL:1

HGVSc / HGVSpc.818C>Tp.Thr273Met

Exon rankExon 3 of 11

missense

Prot: ENSP00000328531.4UniProt: Q12809-2

KCNH2 ENST00000461280.2

TSL:1

HGVSc / HGVSpn.1136C>T

Exon rankExon 3 of 5

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:34
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461876	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:34
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:23376	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Cardiovascular phenotype (3)
1	-	-	Long QT syndrome (1)
1	-	-	Long QT syndrome 2 (1)
1	-	-	Short QT syndrome type 1 (1)
-	-	-	Congenital long QT syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
CardioboostArm	Pathogenic	1.0
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-8.9
GPN-Star score	N/A	8.8
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	2/98	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.0	M
PhyloP100	Pathogenic	9.8
popEVE	Benign	-4.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R	N/A	0.83
VESM-3B	Benign	-13

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

4 abnormal

4 assays found for this variant.

Clinical calibration: 4 functionally abnormal (PS3), 0 functionally normal (BS3).

Protein level

Scores from arrayed automated patch clamp experiment for KCNH2

Arrayed automated patch clamp experiment for KCNH2

• Gene: KCNH2
• Assay type: Direct protein function
• Mechanism: Monoatomic ion transport and Potassium channel activity
• Model system: Immortalized human cells (Homo sapiens)
• Score: 0.200 · p.Thr613Met (assay numbering)

Classified as

PS3 moderateFunctionally abnormalInvestigator-provided functional classes: Abnormal function

+2 more calibrations

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Abnormal function

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Abnormal function

Protein level

Scores from arrayed automated patch clamp experiment for KCNH2

Arrayed automated patch clamp experiment for KCNH2

• Gene: KCNH2
• Assay type: Direct protein function
• Mechanism: Monoatomic ion transport and Potassium channel activity
• Model system: Immortalized human cells (Homo sapiens)
• Score: 0.200 · p.Thr613Met (assay numbering)

Classified as

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Abnormal function

+3 more calibrations

PS3 moderateFunctionally abnormalInvestigator-provided functional classes: Abnormal function

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Abnormal function

PS3 very strongFunctionally abnormalRUO ExCALIBR calibration: PS3 Very Strong (8)

Protein level

Scores from cell surface expression deep mutational scan of KCNH2 in HEK293T cells

Cell surface expression deep mutational scan of KCNH2 in HEK293T cells

• Gene: KCNH2
• Assay type: Reporter
• Mechanism: Protein localization to plasma membrane
• Model system: Immortalized human cells (Homo sapiens)
• Score: 0.00 · p.Thr613Met (assay numbering)

Classified as

PS3 strongFunctionally abnormalInvestigator-provided functional classes: Loss of function

+2 more calibrations

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Loss of function

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Loss of function

Protein level

Scores from cell surface expression deep mutational scan of KCNH2 in HEK293T cells

Cell surface expression deep mutational scan of KCNH2 in HEK293T cells

• Gene: KCNH2
• Assay type: Reporter
• Mechanism: Protein localization to plasma membrane
• Model system: Immortalized human cells (Homo sapiens)
• Score: 0.00 · p.Thr613Met (assay numbering)

Classified as

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Loss of function

+3 more calibrations

PS3 strongFunctionally abnormalInvestigator-provided functional classes: Loss of function

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Loss of function

PS3 strongFunctionally abnormalRUO ExCALIBR calibration: PS3 Strong (4)

Other links and lift over

dbSNP: rs199473524;

hg19: chr7-150648643;

COSMIC: COSV51233401;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar