rs199473419

Variant names:

• chr7-150974809-T-C
• rs199473419
• NM_000238.4:c.209A>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000238.4(KCNH2):​c.209A>G​(p.His70Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000234237: Published functional studies demonstrate a damaging effect on channel trafficking and/or channel function (Chen et al., 1999" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H70N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 2.56
• Publications: 24 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 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000234237: Published functional studies demonstrate a damaging effect on channel trafficking and/or channel function (Chen et al., 1999; Jou et al., 2013; Anderson et al., 2014; Perry et al., 2016); SCV000543479: Experimental studies have shown that this missense change affects KCNH2 function (PMID: 10187793, 21536673, 22396785, 23303164).; SCV002724518: "In vitro analyses of this alteration have suggested both accelerated rate of channel deactivation in the Xenopus oocyte model, and a rate similar to wild type using HEK293 cells (Chen J et al. J. Biol. Chem. 1999;274:10113-8; Anderson CL et al. Nat Commun. 2014;5:5535; Gianulis EC et al. J Biol Chem. 2011;286:22160-9)."
• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.909
• PP5: Variant 7-150974809-T-C is Pathogenic according to our data. Variant chr7-150974809-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67363.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.209A>G	p.His70Arg	missense	Exon 2 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_172056.3		c.209A>G	p.His70Arg	missense	Exon 2 of 9	NP_742053.1	Q12809-5
	KCNH2	NM_001406755.1		c.32A>G	p.His11Arg	missense	Exon 2 of 9	NP_001393684.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.209A>G	p.His70Arg	missense	Exon 2 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.209A>G	p.His70Arg	missense	Exon 2 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000945647.1		c.209A>G	p.His70Arg	missense	Exon 2 of 14	ENSP00000615706.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
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	Uncertain	0.34
CardioboostArm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Benign	0.90
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	0.072
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L
PhyloP100		2.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.82
Sift	Benign	0.17	T
Sift4G	Benign	0.21	T
Polyphen		0.99	D
Vest4		0.72
MVP		0.99
MPC		2.1
ClinPred		0.49	T
GERP RS		4.4
Varity_R		0.67
gMVP		0.97
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs199473419; hg19: chr7-150671897;