rs199473004

chr7-150948938-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.2510A>G(p.Asp837Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D837N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 8.01

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 helix (size 9) in uniprot entity KCNH2_HUMAN there are 5 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 chr7-150948939-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 7-150948938-T-C is Pathogenic according to our data. Variant chr7-150948938-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150948938-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2510A>G	p.Asp837Gly	missense_variant	10/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2510A>G	p.Asp837Gly	missense_variant	10/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1490A>G	p.Asp497Gly	missense_variant	6/11	1
KCNH2	ENST00000684241.1	n.3343A>G		non_coding_transcript_exon_variant	8/13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 08, 2022	The KCNH2 c.2510A>G; p.Asp837Gly variant (rs199473004) is reported in the literature in several individuals affected with long QT syndrome (Lieve 2013, Migdalovich 2011, Mullally 2013, Partemi 2015, Tester 2005). This variant is also reported in ClinVar (Variation ID: 67407), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartate at codon 837 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.959). Functional analyses of the variant protein show abnormal trafficking and gating (Anderson 2014). Additionally, other amino acid substitutions at this codon (Tyr, Asn, His) have been reported in individuals with long QT syndrome (Kapa 2009, Kapplinger 2009, Robyns 2017). Based on available information, this variant is considered to be likely pathogenic. References: Anderson CL et al. Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome. Nat Commun. 2014 Nov 24;5:5535. PMID: 25417810. Kapa S et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. PMID: 19841300. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. PMID: 19716085. Lieve KV et al. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013 Jul;17(7):553-61. PMID: 23631430. Migdalovich D et al. Mutation and gender-specific risk in type 2 long QT syndrome: implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome. Heart Rhythm. 2011 Oct;8(10):1537-43. PMID: 21440677. Mullally J et al. Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations. Heart Rhythm. 2013 Mar;10(3):378-82. PMID: 23174487. Partemi S et al. Genetic and forensic implications in epilepsy and cardiac arrhythmias: a case series. Int J Legal Med. 2015 May;129(3):495-504. PMID: 25119684. Robyns T et al. Individualized corrected QT interval is superior to QT interval corrected using the Bazett formula in predicting mutation carriage in families with long QT syndrome. Heart Rhythm. 2017 Mar;14(3):376-382. PMID: 28212739. Tester DJ et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2(5):507-17. PMID: 15840476. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2018	The D837G pathogenic variant in the KCNH2 gene has been reported previously in association with LQTS, and this variant was absent from 1,488 control alleles (Khositseth et al., 2004; Tester et al., 2005; Partemi et al., 2014). In addition, the NHLBI Exome Sequencing Project reports D837G was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The D837G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species and islocated in the cyclic-nucleotide-binding homology domain (CNBHD). Moreover, functional studies have shown that variants in the CNBHD can cause incorrect folding that can lead to protein instability and ultimately deficient protein trafficking (Li et al., 2016; Anderson et al., 2014). Furthermore, pathogenic missense variants at the same residue (D837N, D837Y), as well as variants in nearby residues (R835W, R835Q, V841L, P846S, P846T) have been reported in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, D837G in the KCNH2 gene is interpreted as a pathogenic variant. -

Long QT syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 08, 2023	The c.2510A>G (p.Asp837Gly) variant in the KCNH2 gene is predicted to replace aspartic acid with glycine at codon 837 (p.Asp837Gly). This variant has been reported in multiple individuals with long QT syndrome (PMID: 21440677, 15851119, 25119684, 20850565, 23631430). Experimental analysis of the variant in cultured cell line proved the deficient protein trafficking and the negative functional impact (PMID: 25417810). Alternative variants disrupting the same amino acid (p.Asp837Asn, p.Asp837Tyr) have been interpreted as pathogenic/likely pathogenic (ClinVar ID: 67405, 67406). The variant is reported in ClinVar (ID: 67407). The variant is absent in the general population database (gnomAD). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.959). Therefore, the c.2510A>G (p.Asp837Gly) variant of KCNH2 has been classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 837 of the KCNH2 protein (p.Asp837Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 21440677, 25119684; Invitae). ClinVar contains an entry for this variant (Variation ID: 67407). 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: 25417810). This variant disrupts the p.Asp837 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19841300, 26669661). 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. -

Long QT syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

May 31, 2018

This variant is interpreted as a Likely Pathogenic, for Long QT syndrome 2, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate => PS3 downgraded in strength to Moderate. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Mutation found in multiple unrelated patients and absent from population databases. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The p.D837G variant (also known as c.2510A>G), located in coding exon 10 of the KCNH2 gene, results from an A to G substitution at nucleotide position 2510. The aspartic acid at codon 837 is replaced by glycine, an amino acid with similar properties, and is located in the cyclic nucleotide binding region of the protein. This variant has been reported in individuals with long QT syndrome (Khositseth A et al. Heart Rhythm. 2004;1(1):60-4; Ambry internal data). Immunoblot data suggest that this variant is a protein trafficking deficient alteration (Anderson CL et al. Nat Commun. 2014;5:5535). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 25, 2022

Variant summary: KCNH2 c.2510A>G (p.Asp837Gly) results in a non-conservative amino acid change located in the Cyclic nucleotide-binding domain (IPR000595) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251458 control chromosomes (gnomAD). c.2510A>G has been reported in the literature in individuals with personal and family history of Arrhythmia (Khositseth_2004, Tester_2005, Mullally_2013, Lieve_2013, Partemi_2015). These data indicate that the variant may be associated with disease. To our knowledge, two publications have shown experimental evidence that the variant impacts protein function: the variant induces a trafficking defect of the mature hERG channel when expressed alone in HEK293 cells, and in a dominant-negative manner when co-expressed with wild-type protein (Anderson_2014). Conformational changes that were detected via NMR spectrometry in E.coli purified protein have been suggested as a cause of this deficiency (Li_2016). Four ClinVar submitters have assessed this variant since 2014: three classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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:15840476;PMID:15851119). 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	0.91
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.011	D;D
Sift4G	Benign	0.20	T;T
Polyphen		0.71	P;D
Vest4		0.87
MutPred		0.91		.;Loss of stability (P = 0.0592);
MVP		1.0
MPC		2.5
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.75
gMVP		0.98

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: rs199473004; hg19: chr7-150646026;