NM_000238.4(KCNH2):c.2675_2679dup (p.Arg894fs) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 12, 2022
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:: RCV001856987.3

Allele description [Variation Report for NM_000238.4(KCNH2):c.2675_2679dup (p.Arg894fs)]

NM_000238.4(KCNH2):c.2675_2679dup (p.Arg894fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_000238.4(KCNH2):c.2675_2679dup (p.Arg894fs)

HGVS:

NC_000007.14:g.150948457_150948461dup
NG_008916.1:g.34466_34470dup
NM_000238.4:c.2675_2679dupMANE SELECT
NM_172057.3:c.1655_1659dup
NP_000229.1:p.Arg894fs
NP_742054.1:p.Arg554fs
LRG_288:g.34466_34470dup
NC_000007.13:g.150645544_150645545insCCTGC
NC_000007.13:g.150645545_150645549dup
NM_000238.3:c.2675_2679dupGCAGG

Protein change:

R554fs

Links:

dbSNP: rs1131692183

NCBI 1000 Genomes Browser:

rs1131692183

Molecular consequence:

NM_000238.4:c.2675_2679dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_172057.3:c.1655_1659dup - 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
SCV002171118	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 12, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10973849, 19862833, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002171118

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 12, 2022)

germline

clinical testing

PubMed (3)
[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

Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.

Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT.

Circulation. 2000 Sep 5;102(10):1178-85.

PubMed [citation]

PMID:: 10973849

The genetic basis of long QT and short QT syndromes: a mutation update.

Hedley PL, Jørgensen P, Schlamowitz S, Wangari R, Moolman-Smook J, Brink PA, Kanters JK, Corfield VA, Christiansen M.

Hum Mutat. 2009 Nov;30(11):1486-511. doi: 10.1002/humu.21106. Review.

PubMed [citation]

PMID:: 19862833

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV002171118.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 430730). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg894Alafs*82) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833).

#	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: Jun 9, 2024

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