NM_000238.4(KCNH2):c.3040C>T (p.Arg1014Ter) AND Long QT syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 22, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000204945.10

Allele description

NM_000238.4(KCNH2):c.3040C>T (p.Arg1014Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_000238.4(KCNH2):c.3040C>T (p.Arg1014Ter)

Other names:

p.R1014*:CGA>TGA

HGVS:

NC_000007.14:g.150947440G>A
NG_008916.1:g.35487C>T
NM_000238.4:c.3040C>TMANE SELECT
NM_172057.3:c.2020C>T
NP_000229.1:p.Arg1014Ter
NP_000229.1:p.Arg1014Ter
NP_742054.1:p.Arg674Ter
LRG_288t1:c.3040C>T
LRG_288:g.35487C>T
LRG_288p1:p.Arg1014Ter
NC_000007.13:g.150644528G>A
NM_000238.2:c.3040C>T
NM_000238.3:c.3040C>T

Protein change:

R1014*

Links:

dbSNP: rs794728403

NCBI 1000 Genomes Browser:

rs794728403

Molecular consequence:

NM_000238.4:c.3040C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_172057.3:c.2020C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000260318	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19862833, 10973849, 14642687, 28492532
SCV002598583	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 12, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10973849, 23631430, 15572053, 32383558 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000260318

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002598583

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 12, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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

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

A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations.

Etheridge SP, Compton SJ, Tristani-Firouzi M, Mason JW.

J Am Coll Cardiol. 2003 Nov 19;42(10):1777-82.

PubMed [citation]

PMID:: 14642687

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000260318.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Arg1014*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with severe and mild long QT syndrome (PMID: 10973849, 14642687). ClinVar contains an entry for this variant (Variation ID: 200518). For these reasons, this variant has been classified as Pathogenic.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002598583.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: KCNH2 c.3040C>T (p.Arg1014X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 165078 control chromosomes. c.3040C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome (example Splawski_2000, Lieve_2013, Westphal _2020). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant causes HERG channel dysfunction by defective trafficking of the mutant protein (Gong_2004). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Jul 23, 2024

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