rs1385959174

Variant names:

• chr7-150948455-C-CGCCT
• rs1385959174
• NM_000238.4:c.2677_2680dupAGGC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000238.4(KCNH2):​c.2677_2680dupAGGC​(p.Arg894GlnfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000087 in 1,149,748 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. R894R) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.05
• Publications: 2 publications found

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]

KCNH2 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 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 7-150948455-C-CGCCT is Pathogenic according to our data. Variant chr7-150948455-C-CGCCT is described in ClinVar as Pathogenic. ClinVar VariationId is 519280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2677_2680dupAGGC	p.Arg894GlnfsTer27	frameshift_variant	Exon 11 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2677_2680dupAGGC	p.Arg894GlnfsTer27	frameshift_variant	Exon 11 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.70e-7 AC: 1 AN: 1149748 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 576204

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25164

American (AMR) AF: 0.00 AC: 0 AN: 38902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18300

East Asian (EAS) AF: 0.00 AC: 0 AN: 20214

South Asian (SAS) AF: 0.00 AC: 0 AN: 82196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4554

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 887130

Other (OTH) AF: 0.00 AC: 0 AN: 43736

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Pathogenic:1

Jul 15, 2020

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:1

Mar 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 22382559). ClinVar contains an entry for this variant (Variation ID: 519280). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg894Glnfs*27) 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). -

Cardiovascular phenotype Pathogenic:1

Jan 23, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2677_2680dupAGGC pathogenic mutation, located in coding exon 11 of the KCNH2 gene, results from a duplication of AGGC at nucleotide position 2677, causing a translational frameshift with a predicted alternate stop codon (p.R894Qfs*27). This alteration (referred to as insertion of AGGC at c.2680_2681) was previously reported in a woman with syncope, torsades de pointes and QTc prolongation in the post-partum period, and was also identified in her asymptomatic mother and sister who were reported to have borderline QTc intervals (Nishimoto O et al. Intern Med. 2012;51(5):461-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
PhyloP100		2.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1385959174; hg19: chr7-150645543;