7-150952481-C-T

Variant names:

• chr7-150952481-C-T
• rs199472912
• NM_000238.4:c.1501G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.1501G>A​(p.Asp501Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging 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. D501H) has been classified as Pathogenic.

• 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: 7.75

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150952481-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 7-150952481-C-T is Pathogenic according to our data. Variant chr7-150952481-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150952481-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1501G>A	p.Asp501Asn	missense_variant	Exon 6 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1501G>A	p.Asp501Asn	missense_variant	Exon 6 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 40

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

not provided Pathogenic:1

Mar 08, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect where p.(D501N) resulted in a 50% reduction in protein trafficking (PMID: 25254353); 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: 25820318, 12402336, 18441445, 19716085, 19352046, 17088455, 26669661, 20486126, 21185501, 29358271, 14998624, 25254353, 25576780, 32383558, 34546463, 30530868, 31737537, 32494459, 36303204, 28794082, 38219013, 36861347, 37324772, 35989994) -

Long QT syndrome Pathogenic:1

May 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 501 of the KCNH2 protein (p.Asp501Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 12402336, 14998624, 17088455, 25254353). ClinVar contains an entry for this variant (Variation ID: 67208). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25254353). This variant disrupts the p.Asp501 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16414944, 19926013). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Oct 29, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D501N variant (also known as c.1501G>A), located in coding exon 6 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1501. The aspartic acid at codon 501 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in multiple individuals with features consistent with long QT syndrome (Jongbloed R et al. Hum Mutat, 2002 Nov;20:382-91; Lupoglazoff JM et al. J Am Coll Cardiol, 2004 Mar;43:826-30; Tan HL et al. Circulation, 2006 Nov;114:2096-103; Nagaoka I et al. Circ J, 2008 May;72:694-9; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Ogawa K et al. Circ. J., 2009 Nov;73:2169-72; Sadrieh A et al. Nat Commun, 2014 Sep;5:5069; Pundi KN et al. Heart Rhythm, 2015 Apr;12:776-81; Roberts JD et al. Circ Arrhythm Electrophysiol, 2017 Aug;10:[ePub ahead of print]; Kwok SY et al. Hong Kong Med J, 2018 Dec;24:561-570; Westphal DS et al. Mol Genet Genomic Med, 2020 Sep;8:e1300). In multiple assays testing KCNH2 function, this variant showed functionally abnormal results (Sadrieh A et al. Nat Commun, 2014 Sep;5:5069; Thomson KL et al. HGG Adv, 2024 Apr;5:100270). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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:12402336;PMID:14998624;PMID:18441445;PMID:19716085). 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	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.2	.;H;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;.
Vest4		1.0
MutPred		0.98		.;Loss of sheet (P = 0.0817);.;
MVP		0.98
MPC		2.1
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.92
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs199472912; hg19: chr7-150649569; COSMIC: COSV105859002;