NM_000238.4(KCNH2):c.3087_3096delinsGC (p.Ser1029fs) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 13, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000631579.4

Allele description [Variation Report for NM_000238.4(KCNH2):c.3087_3096delinsGC (p.Ser1029fs)]

NM_000238.4(KCNH2):c.3087_3096delinsGC (p.Ser1029fs)

Gene:

KCNH2:potassium voltage-gated channel subfamily H member 2 [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_000238.4(KCNH2):c.3087_3096delinsGC (p.Ser1029fs)

HGVS:

NC_000007.14:g.150947384_150947393delinsGC
NG_008916.1:g.35534_35543delinsGC
NM_000238.4:c.3087_3096delinsGCMANE SELECT
NM_172057.3:c.2067_2076delinsGC
NP_000229.1:p.Ser1029fs
NP_742054.1:p.Ser689fs
LRG_288:g.35534_35543delinsGC
NC_000007.13:g.150644472_150644481delinsGC

Protein change:

S1029fs

Links:

dbSNP: rs1554424085

NCBI 1000 Genomes Browser:

rs1554424085

Molecular consequence:

NM_000238.4:c.3087_3096delinsGC - frameshift variant - [Sequence Ontology: SO:0001589]
NM_172057.3:c.2067_2076delinsGC - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000752661	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 13, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27920829, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000752661

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 13, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical and genetic features of Australian families with long QT syndrome: A registry-based study.

Burns C, Ingles J, Davis AM, Connell V, Gray B, Hunt L, McGaughran J, Semsarian C.

J Arrhythm. 2016 Dec;32(6):456-461. Epub 2016 Mar 15.

PubMed [citation]

PMID:: 27920829
PMCID:: PMC5129121

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752661.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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