rs794728438

chr7-150952457-CGAAGGGGATGGCGGCCACCATGTCGAT-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_000238.4(KCNH2):c.1498_1524del(p.Ile500_Phe508del) variant causes a 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 (★★). Synonymous variant affecting the same amino acid position (i.e. I500I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.80

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 15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000238.4
• 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 7-150952457-CGAAGGGGATGGCGGCCACCATGTCGAT-C is Pathogenic according to our data. Variant chr7-150952457-CGAAGGGGATGGCGGCCACCATGTCGAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 200638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150952457-CGAAGGGGATGGCGGCCACCATGTCGAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1498_1524del	p.Ile500_Phe508del	inframe_deletion	6/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1498_1524del	p.Ile500_Phe508del	inframe_deletion	6/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 10, 1995

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2022

Identified in a family with LQTS in the published literature (Curran et al., 1995); Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant yields a protein unable to form functional potassium channels and results in reduced capacity for potassium transport (Sanguinetti et al., 1996); In-frame deletion of 9 amino acids in a non-repeat region and disrupts the third membrane-spanning domain (S3) of KCNH2, causing loss of normal protein function; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10690299, 8700910, 7889573) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 28, 2023

This variant, c.1498_1524del, results in the deletion of 9 amino acid(s) of the KCNH2 protein (p.Ile500_Phe508del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with long QT syndrome (PMID: 7889573). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200638). 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: rs794728438; hg19: chr7-150649545;