rs199473035

Variant names:

• chr7-150945388-G-A
• rs199473035
• NM_000238.4:c.3457C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PS3 PP2 BS2

The NM_000238.4(KCNH2):​c.3457C>T​(p.His1153Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000729 in 1,590,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). ClinVar reports functional evidence for this variant: "SCV002015218: The functional characterization of the H1153Y channel variant in Xenopus oocytes showed a loss of function and no dominant negative effect on wild-type (WT) channels (Limberg, M., 2011). These results concur with a recent study that identified this H1153Y KCNH2 variant in a sudden arrhythmic death syndrome case. The study showed that the H1153Y variant causes a loss of KCNH2 channel function that reduces the current density leading to LQT2. (Farrugia, A. et al., 2021).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1153Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:8 O:2
• Conservation: PhyloP100: 4.75
• Publications: 4 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), G2P, Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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 1 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002015218: The functional characterization of the H1153Y channel variant in Xenopus oocytes showed a loss of function and no dominant negative effect on wild-type (WT) channels (Limberg, M., 2011). These results concur with a recent study that identified this H1153Y KCNH2 variant in a sudden arrhythmic death syndrome case. The study showed that the H1153Y variant causes a loss of KCNH2 channel function that reduces the current density leading to LQT2. (Farrugia, A. et al., 2021).
• 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, short QT syndrome type 1, short QT syndrome, Brugada syndrome, long QT syndrome.
• BS2: High AC in GnomAdExome4 at 112 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.3457C>T	p.His1153Tyr	missense	Exon 15 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.3169C>T	p.His1057Tyr	missense	Exon 13 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.2437C>T	p.His813Tyr	missense	Exon 11 of 11	NP_742054.1	Q12809-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.3457C>T	p.His1153Tyr	missense	Exon 15 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.2437C>T	p.His813Tyr	missense	Exon 11 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.3391C>T	p.His1131Tyr	missense	Exon 15 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000483 AC: 10 AN: 207056 AF XY: 0.0000623

Gnomad AFR exome AF: 0.0000845

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000779 AC: 112 AN: 1438114 Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 67 AN XY: 713072

African (AFR) AF: 0.0000605 AC: 2 AN: 33052

American (AMR) AF: 0.00 AC: 0 AN: 41876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25646

East Asian (EAS) AF: 0.00 AC: 0 AN: 38584

South Asian (SAS) AF: 0.0000969 AC: 8 AN: 82542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50664

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5378

European-Non Finnish (NFE) AF: 0.0000917 AC: 101 AN: 1100990

Other (OTH) AF: 0.00 AC: 0 AN: 59382

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000815 Hom.: 0

Bravo AF: 0.0000416

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000749 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Long QT syndrome (2)
1	1	-	Long QT syndrome 2 (3)
-	2	-	not provided (2)
-	1	-	Cardiac arrhythmia (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Short QT syndrome type 1;C3150943:Long QT syndrome 2 (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
CardioboostArm	Uncertain	0.80
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.89
Sift	Benign	0.042	D
Sift4G	Uncertain	0.045	D
Polyphen		0.91	P
Vest4		0.34
MutPred		0.73		Gain of phosphorylation at H1153 (P = 0.0376)
MVP		0.96
MPC		0.59
ClinPred		0.28	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.57
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs199473035; hg19: chr7-150642476;