NM_000238.4:c.2180_2317del

Variant names:

• chr7-150950248-CCAGCATGCACCAGTGTGTCCCCTGGCGGTGCATGTGTGGTCTTGAACTTCATGGCCAGGGCCCGAAGGCAGCCCTTGGTGGCCCCTCGGAAGGGTTTGCAGTGCTGCAGCAGTGAGCGGTTCAGGTGCAGGCAGATGT-C
• rs1554425226
• NM_000238.4:c.2180_2317del

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM4 PP3 PP5_Moderate

The NM_000238.4(KCNH2):​c.2180_2317del​(p.Asp727_Ala772del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: KCNH2 NM_000238.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000238.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-150950248-CCAGCATGCACCAGTGTGTCCCCTGGCGGTGCATGTGTGGTCTTGAACTTCATGGCCAGGGCCCGAAGGCAGCCCTTGGTGGCCCCTCGGAAGGGTTTGCAGTGCTGCAGCAGTGAGCGGTTCAGGTGCAGGCAGATGT-C is Pathogenic according to our data. Variant chr7-150950248-CCAGCATGCACCAGTGTGTCCCCTGGCGGTGCATGTGTGGTCTTGAACTTCATGGCCAGGGCCCGAAGGCAGCCCTTGGTGGCCCCTCGGAAGGGTTTGCAGTGCTGCAGCAGTGAGCGGTTCAGGTGCAGGCAGATGT-C is described in ClinVar as [Pathogenic]. Clinvar id is 456903.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2180_2317del	p.Asp727_Ala772del	disruptive_inframe_deletion	Exon 9 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2180_2317del	p.Asp727_Ala772del	disruptive_inframe_deletion	Exon 9 of 15	1	NM_000238.4	ENSP00000262186.5

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

Long QT syndrome Pathogenic:1

Jun 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.2180_2317del, results in the deletion of 46 amino acid(s) of the KCNH2 protein (p.Asp727_Ala772del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 456903). This variant disrupts a region of the KCNH2 protein in which other variant(s) (p.Asp774Tyr) have been determined to be pathogenic (PMID: 10973849, 11009462, 18441445). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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: rs1554425226; hg19: chr7-150647336;