rs773724817

chr7-150948861-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000238.4(KCNH2):c.2587C>T(p.Arg863Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,796 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R863R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNH2 NM_000238.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.23

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-150948861-G-A is Pathogenic according to our data. Variant chr7-150948861-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 220208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150948861-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2587C>T	p.Arg863Ter	stop_gained	10/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2587C>T	p.Arg863Ter	stop_gained	10/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1567C>T	p.Arg523Ter	stop_gained	6/11	1
KCNH2	ENST00000684241.1	n.3420C>T		non_coding_transcript_exon_variant	8/13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251266 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135820

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000882 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2021	Reported multiple times in association with LQTS (Van Langen et al., 2003; Nagaoka et al., 2008; Kapa et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as this variant failed to form functional KCNH2 channels (Teng et al., 2004; Akhavan et al., 2005; Yao et al., 2009); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 220208; ClinVar); This variant is associated with the following publications: (PMID: 15840476, 21143190, 19716085, 25525159, 24993425, 24366185, 14714110, 18441445, 19841300, 15961404, 19324319, 12566525, 22515331) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2016	- -

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 220208). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 12566525, 14714110, 15840476, 22515331). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs773724817, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg863*) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 28, 2022	Variant summary: KCNH2 c.2587C>T (p.Arg863X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.9e-06 in 254304 control chromosomes (gnomAD). c.2587C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome (examples: Van Langen_2003, Teng_2004, Kapa_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Teng_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 10, 2020

The p.Arg863X variant in KCNH2 has been reported in 3 individuals with Long QT syndrome (LQTS), including a presumed de novo occurrence, and in 1 individual referred for LQTS testing (Teng 2004 PMID: 14714110, Yao 2009 PMID: 19324319, Tester 2005 PMID: 15840476, Van Langen 2003 PMID: 12566525, Zamorano-Leon 2012 PMID: 22515331). This variant segregated with LQTS in 5 relatives from 1 family (Teng 2004 PMID: 14714110). It has also been reported by other clinical laboratories in ClinVar (Variation ID 220208) and it has been identified in 0.004% (1/24956) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact on protein function (Teng 2004 PMID: 14714110, Yao 2009 PMID: 19324319). This nonsense variant leads to a premature termination codon at position 863, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KCNH2 gene is an established disease mechanism in LQTS. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PVS1, PP1_Moderate, PM2, PS4_Supporting, PM6, PS3_supporting. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2018

The p.R863* pathogenic mutation (also known as c.2587C>T), located in coding exon 10 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2587. This changes the amino acid from an arginine to a stop codon within coding exon 10. This mutation has been reported in unrelated individuals with long QT syndrome (LQTS), and has been reported to segregate with disease in at least one family. In addition, this mutation has been reported to occur de novo in an affected individual, and to result in abnormal protein trafficking and ion channel function in in vitro studies (Van Langen IM et al. J Med Genet. 2003;40:141-5; Teng S et al. J Mol Med. 2004;82:189-96; Yao Y et al. Heart Rhythm. 2009;6:553-60; Zamorano-León JJ et al. J Neurogenet. 2012;26:382-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	44
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.99
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs773724817; hg19: chr7-150645949; COSMIC: COSV51136691; COSMIC: COSV51136691;