chr7-150948981-G-A

Variant names:

• chr7-150948981-G-A
• rs199473538
• NM_000238.4:c.2467C>T
• KCNH2 p.Arg823Trp

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 17 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPM5PP3_StrongPP5_Strong

The NM_000238.4(KCNH2):c.2467C>T (p.Arg823Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,828 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000731561: "In vitro functional studies provide some evidence that the p.Arg823Trp variant may impact protein function (Ficker 2002, Roti 2002, Anderson 2006)."" 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.R823Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 418246) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R823L: Uncertain_significance (ClinVar VariationId 2415860, 1 star); p.R823P: Uncertain_significance (ClinVar VariationId 1450592, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • 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:6 O:1
• Conservation: PhyloP100: 0.246
• Publications: 11 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000731561: "In vitro functional studies provide some evidence that the p.Arg823Trp variant may impact protein function (Ficker 2002, Roti 2002, Anderson 2006)."; SCV000283973: Experimental studies have shown that this missense change affects KCNH2 function (PMID: 11741928, 16432067, 23303164).; SCV001338454: "In experimental studies, the variant was found to result in deficient trafficking, reduced repolarization, and inability to be rescued by channel blockers (Jou_2013, Anderson_2006, Ficker_2002)."; SCV000737553: Studies in cultured cell lines and zebrafish embryos suggested this alteration causes protein traffic deficiency that would compromise channel functions (Ficker E et al, J. Biol. Chem. 2002 Feb; 277(7):4989-98; Anderson CL et al, Circulation 2006 Jan; 113(3):365-73; Jou CJ et al, Circ. Res. 2013 Mar; 112(5):826-30).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 7 pathogenic, 0 benign (OR vs. background: 75.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R823Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 418246); Other variants at the same amino acid residue (not pathogenic): p.R823L: Uncertain_significance (ClinVar VariationId 2415860, 1 star); p.R823P: Uncertain_significance (ClinVar VariationId 1450592, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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.2467C>T p.Arg823Trp	missense	Exon 10 of 15	Prot: NP_000229.1 UniProt:
	KCNH2 NM_001406753.1		c.2179C>T p.Arg727Trp	missense	Exon 8 of 13	Prot: NP_001393682.1 UniProt:
	KCNH2 NM_172057.3		c.1447C>T p.Arg483Trp	missense	Exon 6 of 11	Prot: NP_742054.1 UniProt:

KCNH2 NM_000238.4

MANE Select

HGVSc / HGVSpc.2467C>Tp.Arg823Trp

Exon rankExon 10 of 15

missense

Prot: NP_000229.1UniProt: Q12809-1

KCNH2 NM_001406753.1

HGVSc / HGVSpc.2179C>Tp.Arg727Trp

Exon rankExon 8 of 13

missense

Prot: NP_001393682.1UniProt: Q12809-7

KCNH2 NM_172057.3

HGVSc / HGVSpc.1447C>Tp.Arg483Trp

Exon rankExon 6 of 11

missense

Prot: NP_742054.1UniProt: Q12809-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNH2 ENST00000262186.10	TSL:1MANE Select	c.2467C>T p.Arg823Trp	missense	Exon 10 of 15	Prot: ENSP00000262186.5 UniProt:
	KCNH2 ENST00000330883.9	TSL:1	c.1447C>T p.Arg483Trp	missense	Exon 6 of 11	Prot: ENSP00000328531.4 UniProt:
	KCNH2 ENST00000713710.1		c.2401C>T p.Arg801Trp	missense	Exon 10 of 15	Prot: ENSP00000519013.1 UniProt:

KCNH2 ENST00000262186.10

TSL:1MANE Select

HGVSc / HGVSpc.2467C>Tp.Arg823Trp

Exon rankExon 10 of 15

missense

Prot: ENSP00000262186.5UniProt: Q12809-1

KCNH2 ENST00000330883.9

TSL:1

HGVSc / HGVSpc.1447C>Tp.Arg483Trp

Exon rankExon 6 of 11

missense

Prot: ENSP00000328531.4UniProt: Q12809-2

KCNH2 ENST00000713710.1

HGVSc / HGVSpc.2401C>Tp.Arg801Trp

Exon rankExon 10 of 15

missense

Prot: ENSP00000519013.1UniProt: A0AAQ5BGR0

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: 0.00000659	AC:1	Hom:0	AN:151804	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251454	Cov:
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461828	Cov:32
GnomAD4 genome Warning	AF: 0.00000659	AC:1	Hom:0	AN:151804	Cov:32

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
CardioboostArm	Pathogenic	1.0
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.76	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-9.8
GPN-Star score	N/A	9.8
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	5/95	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.1	H
PhyloP100	Benign	0.25
popEVE	Benign	-4.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.1	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.93
VESM-3B	Benign	-13

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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.

2 abnormal

2 assays found for this variant.

Clinical calibration: 2 functionally abnormal (PS3), 0 functionally normal (BS3).

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.Arg823Trp (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.Arg823Trp (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: rs199473538;

hg19: chr7-150646069;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar