chr7-150951583-C-T

Variant names:

• chr7-150951583-C-T
• rs199473522
• NM_000238.4:c.1810G>A
• KCNH2 p.Gly604Ser

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 18 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_StrongPP5_Strong

The NM_000238.4(KCNH2):c.1810G>A (p.Gly604Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: 7.79). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000259591: Experimental studies have shown that this missense change affects KCNH2 function (PMID:18386051, 25417810)." 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.G604V: Likely_pathogenic (ClinVar VariationId 200741, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G604D: not_provided (ClinVar VariationId 67282); p.G604= (synonymous): Likely_benign (ClinVar VariationId 926709, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.79
• Publications: 41 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 18 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000259591: Experimental studies have shown that this missense change affects KCNH2 function (PMID: 18386051, 25417810).; SCV002711946: "In assays testing KCNH2 function, this variant showed a functionally abnormal result" (Huo J et al. Pflugers Arch. 2008;456:917-28; Anderson CL et al. Nat Commun. 2014;5:5535).
	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: 16 pathogenic, 0 benign (OR vs. background: 165.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	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.G604V: Likely_pathogenic (ClinVar VariationId 200741, 1 star); Other variants at the same amino acid residue (not pathogenic): p.G604D: not_provided (ClinVar VariationId 67282); p.G604= (synonymous): Likely_benign (ClinVar VariationId 926709, 2 stars)
	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.1810G>A p.Gly604Ser	missense	Exon 7 of 15	Prot: NP_000229.1 UniProt:
	KCNH2 NM_001406753.1		c.1522G>A p.Gly508Ser	missense	Exon 5 of 13	Prot: NP_001393682.1 UniProt:
	KCNH2 NM_172056.3		c.1810G>A p.Gly604Ser	missense	Exon 7 of 9	Prot: NP_742053.1 UniProt:

KCNH2 NM_000238.4

MANE Select

HGVSc / HGVSpc.1810G>Ap.Gly604Ser

Exon rankExon 7 of 15

missense

Prot: NP_000229.1UniProt: Q12809-1

KCNH2 NM_001406753.1

HGVSc / HGVSpc.1522G>Ap.Gly508Ser

Exon rankExon 5 of 13

missense

Prot: NP_001393682.1UniProt: Q12809-7

KCNH2 NM_172056.3

HGVSc / HGVSpc.1810G>Ap.Gly604Ser

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.1810G>A p.Gly604Ser	missense	Exon 7 of 15	Prot: ENSP00000262186.5 UniProt:
	KCNH2 ENST00000330883.9	TSL:1	c.790G>A p.Gly264Ser	missense	Exon 3 of 11	Prot: ENSP00000328531.4 UniProt:
	KCNH2 ENST00000461280.2	TSL:1	n.1108G>A	non_coding_transcript_exon	Exon 3 of 5	Prot:

KCNH2 ENST00000262186.10

TSL:1MANE Select

HGVSc / HGVSpc.1810G>Ap.Gly604Ser

Exon rankExon 7 of 15

missense

Prot: ENSP00000262186.5UniProt: Q12809-1

KCNH2 ENST00000330883.9

TSL:1

HGVSc / HGVSpc.790G>Ap.Gly264Ser

Exon rankExon 3 of 11

missense

Prot: ENSP00000328531.4UniProt: Q12809-2

KCNH2 ENST00000461280.2

TSL:1

HGVSc / HGVSpn.1108G>A

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:34
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:34

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41958	0.00	0	66888

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	27
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
CardioboostArm	Pathogenic	1.0
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-7.9
GPN-Star score	N/A	7.9
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	2/98	disease causing (ClinVar)
MutationAssessor	Uncertain	2.6	M
PhyloP100	Pathogenic	7.8
popEVE	Benign	-4.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.0	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.85
VESM-3B	Benign	-11

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.

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: 0.150 · p.Gly604Ser (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: 0.150 · p.Gly604Ser (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.Gly604Ser (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.Gly604Ser (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: rs199473522;

hg19: chr7-150648671;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar