7-150947425-TG-TGGGGGGGG

Variant names:

• chr7-150947425-T-TGGGGGGG
• rs1554424138
• NM_000238.4:c.3054_3055insCCCCCCC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000238.4(KCNH2):​c.3054_3055insCCCCCCC​(p.Thr1019ProfsTer102) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P1018P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.166
• Publications: 0 publications found

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]

KCNH2 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 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 7-150947425-T-TGGGGGGG is Pathogenic according to our data. Variant chr7-150947425-T-TGGGGGGG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3076029.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.3054_3055insCCCCCCC	p.Thr1019ProfsTer102	frameshift_variant	Exon 13 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.3054_3055insCCCCCCC	p.Thr1019ProfsTer102	frameshift_variant	Exon 13 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1287706 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 638566

African (AFR) AF: 0.00 AC: 0 AN: 29722

American (AMR) AF: 0.00 AC: 0 AN: 35466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24122

East Asian (EAS) AF: 0.00 AC: 0 AN: 33826

South Asian (SAS) AF: 0.00 AC: 0 AN: 77214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 981454

Other (OTH) AF: 0.00 AC: 0 AN: 53956

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital long QT syndrome Pathogenic:1

Jan 31, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr1019fs variant in KCNH2 has not been previously reported in individuals with long QT syndrome. Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1019 and leads to a premature termination codon 102 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KCNH2 gene is associated with long QT syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Thr1019fs variant is likely pathogenic for long QT syndrome in an autosomal dominant manner based on its predicted impact to the protein.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17

Splicing

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

Other links and lift over

dbSNP: rs1554424138; hg19: chr7-150644513;