rs748706373

chr7-150947610-CAG-C

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.2959_2960del(p.Leu987ValfsTer131) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L987L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.15

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 7-150947610-CAG-C is Pathogenic according to our data. Variant chr7-150947610-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 200693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150947610-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2959_2960del	p.Leu987ValfsTer131	frameshift_variant	12/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2959_2960del	p.Leu987ValfsTer131	frameshift_variant	12/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1939_1940del	p.Leu647ValfsTer131	frameshift_variant	8/11	1
KCNH2	ENST00000684241.1	n.3792_3793del		non_coding_transcript_exon_variant	10/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245698 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133700

Gnomad AFR exome AF: 0.00

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: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460446 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726488

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic (ClinVar Variant ID# 200693; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 23098067, 19841300, 19165230, 28861002, 19716085, 10973849, 26669661, 21737021) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	KCNH2: PVS1, PM2, PS4:Moderate -

Cardiovascular phenotype Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 18, 2018	The c.2959_2960delCT pathogenic mutation, located in coding exon 12 of the KCNH2 gene, results from a deletion of two nucleotides between positions 2959 and 2960, causing a translational frameshift with a predicted alternate stop codon (p.L987Vfs*131). This alteration was first reported in a family with Romano-Ward syndrome (Splawski I et al. Circulation. 2000;102(10):1178-85 (reported as P986fs/130). This alteration has also been detected in cohorts submitted for long QT syndrome genetic testing (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Du Pre BC et al. Front Physiol, 2017 Aug;8:590). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2017	Variant summary: The KCNH2 c.2959_2960delCT (p.Leu987Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent KCNH2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 2/98624 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNH2 variant (0.0001233). Multiple publications have cited the variant in affected individuals diagnosed with LQTS. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Long QT syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Sep 02, 2022

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 (MIM#613688). Gain of function is also a known mechanism associated with short QT syndrome 1 (MIM#609620) (OMIM, PMIDs: 10753933, 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) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many frameshift variants downstream have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with long QT syndrome, and as likely pathogenic/pathogenic (PMID: 32893267, ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Leu987Valfs*131) 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). This variant is present in population databases (rs748706373, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with long QT syndrome (PMID: 10973849, 19716085, 23098067, 26669661). This variant is also known as p.P986fs/130. ClinVar contains an entry for this variant (Variation ID: 200693). -

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

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

KCNH2 NM_000238.3 exon 12 p.Leu987Valfs*131 (c.2959_2960del): This variant has been reported in the literature in at least 6 individuals with a clinical suspicion or diagnosis of Long QT syndrome (also reported as P986fs; Splawski 2000 PMID:10973849, Kapplinger 2009 PMID:19716085, Stattin 2012 PMID:23098067, Itoh 2016 PMID:26669661). This variant is present in 0.0009% (1/110530) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/7-150644698-CAG-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:200693). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a deletion of 2 nucleotides beginning at position 2959 and creates a premature stop codon 131 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Hedley 2009 PMID:19862833). In summary, this variant is classified as pathogenic. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 19, 2018

This variant (also known as p.P986fs+130X in the literature) resuolts in the deletion of 2 nucleotides in exon 12 of the KCNH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals from three families affected with long QT syndrome (PMID: 10973849, 26669661) and in individuals referred for long QT testing (PMID: 19716085, 23098067). This variant has been identified in 1/241050 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs748706373; hg19: chr7-150644698;