rs199472930

Variant names:

• chr7-150951616-T-C
• rs199472930
• NM_000238.4:c.1777A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000238.4(KCNH2):​c.1777A>G​(p.Ile593Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I593T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 2.56
• Publications: 3 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), Ambry Genetics, G2P
• 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: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 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 chr7-150951615-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67270.
• 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, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-150951616-T-C is Pathogenic according to our data. Variant chr7-150951616-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 67268.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.1777A>G	p.Ile593Val	missense	Exon 7 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.1489A>G	p.Ile497Val	missense	Exon 5 of 13	NP_001393682.1
	KCNH2	NM_172056.3		c.1777A>G	p.Ile593Val	missense	Exon 7 of 9	NP_742053.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1777A>G	p.Ile593Val	missense	Exon 7 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.757A>G	p.Ile253Val	missense	Exon 3 of 11	ENSP00000328531.4
	KCNH2	ENST00000461280.2	TSL:1	n.1075A>G		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 06, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in an individual with long QT syndrome; however, detailed clinical information and segregation data were not provided (PMID: 18441445); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32431610, 18441445)

Congenital long QT syndrome Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:18441445). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
CardioboostArm	Uncertain	0.88
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.026
Eigen_PC	Benign	0.035
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.96	L
PhyloP100		2.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.78	N
REVEL	Pathogenic	0.72
Sift	Benign	0.068	T
Sift4G	Benign	0.15	T
Polyphen		0.067	B
Vest4		0.34
MutPred		0.80		Gain of helix (P = 0.0425)
MVP		1.0
MPC		1.5
ClinPred		0.87	D
GERP RS		4.3
Varity_R		0.12
gMVP		0.82
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.93		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199472930; hg19: chr7-150648704;