chr7-150951679-C-T

Variant names:

• chr7-150951679-C-T
• rs9333649
• NM_000238.4:c.1714G>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.1714G>A​(p.Gly572Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000234114: Published functional studies demonstrate a dominant-negative effect that leads to a loss of normal potassium ion channel function (Anderson et al., 2006; Zhao et al., 2009; Jou et al., 2013; Mahati et al., 2016); SCV000737642: "In vitro functional studies have reported this alteration to result in abnormal channel trafficking and dominant negative effect leading to loss of normal KCNH2 ion channel function (Anderson CL et al. Circulation. 2006; 113(3):365-73; Zhao JT et al. J Cardiovasc Electrophysiol. 2009; 20(8):923-30; Jou CJ et al. Circ Res. 2013; 112(5):826-30; Liu L et al. Front Physiol, 2016 Dec;7:650)."; SCV000752630: Experimental studies have shown that this missense change affects KCNH2 function (PMID:16432067, 19490267, 23303164, 27803431, 28082916).; SCV001451615: Co-expression of the p.Gly572Ser variant and wild type KCNH2 cDNA in continuous cell lines demonstrated that the p.Gly572Ser variant channel did not undergo glycosylation within the Golgi and has a dominant negative effect on the trafficking of KCNH2 to the cellular membrane, causing its retention in the ER and Golgi, and thereby reduction of channel activity with a reduction in current density of 90% compared to wild type (Anderson et al. 2006; Zhao et al. 2009; Liu et al. 2016).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G572D) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 7.54
• Publications: 42 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: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000234114: Published functional studies demonstrate a dominant-negative effect that leads to a loss of normal potassium ion channel function (Anderson et al., 2006; Zhao et al., 2009; Jou et al., 2013; Mahati et al., 2016); SCV000737642: "In vitro functional studies have reported this alteration to result in abnormal channel trafficking and dominant negative effect leading to loss of normal KCNH2 ion channel function (Anderson CL et al. Circulation. 2006; 113(3):365-73; Zhao JT et al. J Cardiovasc Electrophysiol. 2009; 20(8):923-30; Jou CJ et al. Circ Res. 2013; 112(5):826-30; Liu L et al. Front Physiol, 2016 Dec;7:650)."; SCV000752630: Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16432067, 19490267, 23303164, 27803431, 28082916).; SCV001451615: Co-expression of the p.Gly572Ser variant and wild type KCNH2 cDNA in continuous cell lines demonstrated that the p.Gly572Ser variant channel did not undergo glycosylation within the Golgi and has a dominant negative effect on the trafficking of KCNH2 to the cellular membrane, causing its retention in the ER and Golgi, and thereby reduction of channel activity with a reduction in current density of 90% compared to wild type (Anderson et al. 2006; Zhao et al. 2009; Liu et al. 2016).
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 29 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150951679-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 14429.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 7-150951679-C-T is Pathogenic according to our data. Variant chr7-150951679-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 67248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1714G>A	p.Gly572Ser	missense	Exon 7 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.1426G>A	p.Gly476Ser	missense	Exon 5 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.1714G>A	p.Gly572Ser	missense	Exon 7 of 9	NP_742053.1	Q12809-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1714G>A	p.Gly572Ser	missense	Exon 7 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.694G>A	p.Gly232Ser	missense	Exon 3 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000461280.2	TSL:1	n.1012G>A		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251312 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152354 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74498

African (AFR) AF: 0.0000240 AC: 1 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Long QT syndrome 2 (4)
3	-	-	not provided (3)
1	-	-	Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Long QT syndrome (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.83		Gain of disorder (P = 0.0657)
MVP		1.0
MPC		2.2
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9333649; hg19: chr7-150648767;