7-150951507-T-C

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. N629T) 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 hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 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 chr7-150951507-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 67314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1886A>G	p.Asn629Ser	missense_variant	7/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1886A>G	p.Asn629Ser	missense_variant	7/15	1	NM_000238.4	P1

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

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Mar 11, 2018	- -

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 15, 2021	This sequence change replaces asparagine with serine at codon 629 of the KCNH2 protein (p.Asn629Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. For these reasons, this variant has been classified as Pathogenic. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16432067, 23303164, 25417810). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67315). This variant is also known as A2069G (N629S). 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 not present in population databases (ExAC no frequency). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 09, 2017

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

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

-

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
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	26
Dann	Uncertain	1.0
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
MutationTaster	Benign	0.96	D;D;D;D
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;