NM_000238.4(KCNH2):c.3108_3112dup (p.Val1038fs) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 17, 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:: RCV001218782.7

Allele description [Variation Report for NM_000238.4(KCNH2):c.3108_3112dup (p.Val1038fs)]

NM_000238.4(KCNH2):c.3108_3112dup (p.Val1038fs)

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.3108_3112dup (p.Val1038fs)

HGVS:

NC_000007.14:g.150947369_150947373dup
NG_008916.1:g.35555_35559dup
NM_000238.4:c.3108_3112dupMANE SELECT
NM_172057.3:c.2088_2092dup
NP_000229.1:p.Val1038fs
NP_742054.1:p.Val698fs
LRG_288t1:c.3108_3112dup
LRG_288:g.35555_35559dup
NC_000007.13:g.150644455_150644456insCGTCG
NC_000007.13:g.150644457_150644461dup
NM_000238.3:c.3108_3112dup

Protein change:

V1038fs

Links:

dbSNP: rs1800936242

NCBI 1000 Genomes Browser:

rs1800936242

Molecular consequence:

NM_000238.4:c.3108_3112dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_172057.3:c.2088_2092dup - 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
SCV001390685	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 17, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15840476, 16923798, 10973849, 19862833, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001390685

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 17, 2022)

germline

clinical testing

PubMed (5)
[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

Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.

Tester DJ, Will ML, Haglund CM, Ackerman MJ.

Heart Rhythm. 2005 May;2(5):507-17.

PubMed [citation]

PMID:: 15840476

C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3epsilon.

Choe CU, Schulze-Bahr E, Neu A, Xu J, Zhu ZI, Sauter K, Bähring R, Priori S, Guicheney P, Mönnig G, Neapolitano C, Heidemann J, Clancy CE, Pongs O, Isbrandt D.

Hum Mol Genet. 2006 Oct 1;15(19):2888-902. Epub 2006 Aug 21.

PubMed [citation]

PMID:: 16923798

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001390685.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNH2 function (PMID: 16923798). ClinVar contains an entry for this variant (Variation ID: 947666). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 15840476, 16923798). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val1038Alafs*21) 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: Feb 14, 2024

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