7-150951507-T-C

Variant names:

• chr7-150951507-T-C
• rs199472957
• NM_000238.4:c.1886A>G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.1886A>G​(p.Asn629Ser) variant causes a missense change. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N629D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 6.12

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 18 ACMG points.

• PM1: In a intramembrane_region Pore-forming; Name=Segment H5 (size 20) in uniprot entity KCNH2_HUMAN there are 23 pathogenic changes around while only 0 benign (100%) 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 chr7-150951508-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 7-150951507-T-C is Pathogenic according to our data. Variant chr7-150951507-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 67315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951507-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1886A>G	p.Asn629Ser	missense_variant	Exon 7 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1886A>G	p.Asn629Ser	missense_variant	Exon 7 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Pathogenic:2

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Long QT syndrome 2 (LQTS; MIM#613688). Gain of function is also a known mechanism associated with Short QT syndrome 1 (MIM#609620) (OMIM, PMID: 10753933; PMID: 21777565). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional ion transport domain, within the pore (Uniprot, PMID: 16432067). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Both p.(Asn629Thr) and p.(Asn629Asp) have been reported pathogenic for LQTS. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals from various ethnicities with LQTS (ClinVar, PMID: 24606995, 19716085, 26063740), and has also been reported in and individual who suffered a sudden cardiac death who had a variant in the DSG2 gene that was regarded likely benign (PMID: 29016939). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies with transfected HEK293 cells showed that the mutant impaired protein trafficking (PMID: 16432067). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 11, 2018

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

- -

Long QT syndrome Pathogenic:2

Jan 15, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The KCNH2 c.1886A>G (p.Asn629Ser) variant involves the alteration of a conserved nucleotide located in the Ion transport domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 277188 control chromosomes. Multiple publications cite the variant in affected individuals (Koponen_2015. Moss_2002, Larsen_2001, Satler_1998, Gao_2016). Functional studies report the variant to result in abnormal trafficking (Anderson_2006), and diminished repolarization (Jou_2013). Additionally, other variants at the same codon position (N629D, N629K, N629I, N629T) have also been reported in affected individuals, supporting a functional role of the position. One clinical diagnostic laboratories/reputable database has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 629 of the KCNH2 protein (p.Asn629Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9544837, 11854117, 18808722, 24606995, 26063740). It has also been observed to segregate with disease in related individuals. This variant is also known as A2069G (N629S). ClinVar contains an entry for this variant (Variation ID: 67315). 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: 16432067, 23303164, 25417810). This variant disrupts the p.Asn629 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 16432067, 17905336, 19841300, 22573844, 25417810). 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. -

not provided Pathogenic:1

May 09, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The N629S pathogenic variant in the KCNH2 gene has previously been reported in association with LQTS (Satler et al., 1998; Larsen et al., 2001; Kapplinger et al., 2009; Zhang et al., 2008; Moss et al., 2002; Goldenberg et al., 2011; Christiansen et al., 2014; Riuro et al., 2014). In addition, different pathogenic missense variants affecting the same codon (N629T, N629I) have also been reported in association with LQTS (Chung et al., 2007; Kapplinger et al., 2009; Giudicessi et al., 2012). The N629S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although N629S is a conservative amino acid substitution, it occurs within the selectivity filter motif of the pore region at a position that is conserved across species. Functional studies report N629S affects protein-trafficking causing a dominant-negative effect on the normal protein complex, resulting in loss of normal ion channel function (Anderson et al., 2006). Finally, pathogenic/likely pathogenic variants in nearby residues (N633S, N633I, T634I, T634S) have been reported in HGMD in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein. -

Short QT syndrome type 1;C3150943:Long QT syndrome 2 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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:9544837;PMID:11468227;PMID:11668638;PMID:11854117;PMID:16432067;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	0.93
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	.;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D;D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;.
Sift4G	Benign	0.070	T;T;T
Polyphen		0.94	P;D;.
Vest4		0.93
MutPred		0.89		.;Gain of disorder (P = 0.0527);.;
MVP		0.95
MPC		1.8
ClinPred		0.99	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.97

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: rs199472957; hg19: chr7-150648595;