chr7-150947795-GC-G

Variant names:

• chr7-150947795-GC-G
• rs794728455
• NM_000238.4:c.2775delG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000238.4(KCNH2):​c.2775delG​(p.Pro926ArgfsTer48) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000797 in 1,380,020 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. GP925V?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000080 (0 hom.)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -1.37

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-150947795-GC-G is Pathogenic according to our data. Variant chr7-150947795-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 1074305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150947795-GC-G is described in Lovd as [Pathogenic]. Variant chr7-150947795-GC-G is described in Lovd as [Pathogenic]. Variant chr7-150947795-GC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2775delG	p.Pro926ArgfsTer48	frameshift_variant	Exon 12 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2775delG	p.Pro926ArgfsTer48	frameshift_variant	Exon 12 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.1755delG	p.Pro586ArgfsTer48	frameshift_variant	Exon 8 of 11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3608delG		non_coding_transcript_exon_variant	Exon 10 of 13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000235 AC: 3 AN: 127658 Hom.: 0 AF XY: 0.0000287 AC XY: 2 AN XY: 69796

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: 0.0000460

Gnomad FIN exome AF: 0.000149

Gnomad NFE exome AF: 0.0000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000797 AC: 11 AN: 1380020 Hom.: 0 Cov.: 36 AF XY: 0.0000118 AC XY: 8 AN XY: 680358

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000401

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.0000823

Gnomad4 NFE exome AF: 0.00000558

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:2

Nov 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Pro926Argfs*48) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 16414944). ClinVar contains an entry for this variant (Variation ID: 1074305). For these reasons, this variant has been classified as Pathogenic. -

Aug 23, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide 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. This variant has been reported in individual(s) affected with long QT syndrome (PMID: 16414944, 32893267). This variant has been identified in 3/127658 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Sep 20, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2775delG pathogenic mutation, located in coding exon 12 of the KCNH2 gene, results from a deletion of one nucleotide at nucleotide position 2775, causing a translational frameshift with a predicted alternate stop codon (p.P926Rfs*48). This variant has been detected in a long QT syndrome cohort (Napolitano C et al. JAMA, 2005 Dec;294:2975-80). 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. -

Cardiac arrhythmia Pathogenic:1

Jun 29, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide 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. This variant has been reported in individual(s) affected with long QT syndrome (PMID: 16414944, 32893267). This variant has been identified in 3/127658 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease (clinicalgenome.org). Based on the 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: rs794728455; hg19: chr7-150644883;