rs1554424620

Positions:

• chr7-150948449-TCCGTGCG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000238.4(KCNH2):​c.2680_2686del​(p.Arg894ThrfsTer78) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. 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: 30)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.08

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 12 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 7-150948449-TCCGTGCG-T is Pathogenic according to our data. Variant chr7-150948449-TCCGTGCG-T is described in ClinVar as [Pathogenic]. Clinvar id is 519378.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2680_2686del	p.Arg894ThrfsTer78	frameshift_variant	11/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2680_2686del	p.Arg894ThrfsTer78	frameshift_variant	11/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1660_1666del	p.Arg554ThrfsTer78	frameshift_variant	7/11	1
KCNH2	ENST00000684241.1	n.3513_3519del		non_coding_transcript_exon_variant	9/13

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2017

The c.2680_2686delCGCACGG pathogenic mutation, located in coding exon 11 of the KCNH2 gene, results from a deletion of 7 nucleotides at nucleotide positions 2680 to 2686, causing a translational frameshift with a predicted alternate stop codon (p.R894Tfs*78). Translational frameshift alterations in this region have been reported in patients with long QT syndrome (Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Hedley PL et al. Hum. Mutat., 2009 Nov;30:1486-511). 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554424620; hg19: chr7-150645537;