rs1554424085

chr7-150947383-GCCGACCCGGG-GGC

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000238.4(KCNH2):c.3087_3096delinsGC(p.Ser1029ArgfsTer87) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.877

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 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-150947384-CCGACCCGGG-GC is Pathogenic according to our data. Variant chr7-150947384-CCGACCCGGG-GC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526924.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.3087_3096delinsGC	p.Ser1029ArgfsTer87	frameshift_variant	13/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.3087_3096delinsGC	p.Ser1029ArgfsTer87	frameshift_variant	13/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.2067_2076delinsGC	p.Ser689ArgfsTer87	frameshift_variant	9/11	1
KCNH2	ENST00000684241.1	n.3920_3929delinsGC		non_coding_transcript_exon_variant	11/13

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 13, 2020

While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the KCNH2 protein. Other variant(s) that disrupt this region (p.Glu1119*) have been determined to be pathogenic (PMID: 27920829, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 526924). This sequence change results in a premature translational stop signal in the KCNH2 gene (p.Ser1029Argfs*87). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 131 amino acids of the KCNH2 protein. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 15, 2019

Variant summary: KCNH2 c.3087_3096delinsGC (p.Ser1029ArgfsX87) results in a premature termination codon, predicted to cause a truncation of the encoded protein, however may not result in nonsense mediated decay. While the effect of this variant is unknown, mutations in the c-terminal domain may impact protein trafficing (Kupershmidt_2002). The variant was absent in 145596 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3087_3096delinsGC in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic variant. -

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: rs1554424085; hg19: chr7-150644472;