rs199473018

Variant names:

• chr7-150947493-T-A
• rs199473018
• NM_000238.4:c.2987A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150947493-T-A
• chr7-150947493-T-C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.2987A>T​(p.Asn996Ile) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N996S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 2.51
• Publications: 29 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 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 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, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 7-150947493-T-A is Pathogenic according to our data. Variant chr7-150947493-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2987A>T	p.Asn996Ile	missense_variant	Exon 13 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2987A>T	p.Asn996Ile	missense_variant	Exon 13 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Pathogenic:2

Feb 24, 2020

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_Supporting, PM2, PP2, PP3 -

not provided Pathogenic:1

Dec 13, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); Published functional studies suggest the variant reduces channel current, prolongs action potentials, and decreases trafficking of channels to the cell's surface (Bellin M et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15851119, 15840476, 19841300, 22581653, 31737537, 22949429, 24213244) -

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:15840476;PMID:15851119;PMID:19841300). 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
CardioboostArm	Uncertain	0.64
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	.;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	.;L
PhyloP100		2.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		0.96	D;P
Vest4		0.79
MutPred		0.81		.;Gain of sheet (P = 0.0016);
MVP		0.89
MPC		0.77
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.61
gMVP		0.75
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: -10

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

Other links and lift over

dbSNP: rs199473018; hg19: chr7-150644581;