NM_000238.4(KCNH2):c.1900A>C (p.Thr634Pro) AND Long QT syndrome 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 19, 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:: RCV002472021.1

Allele description [Variation Report for NM_000238.4(KCNH2):c.1900A>C (p.Thr634Pro)]

NM_000238.4(KCNH2):c.1900A>C (p.Thr634Pro)

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.1900A>C (p.Thr634Pro)

HGVS:

NC_000007.14:g.150951493T>G
NG_008916.1:g.31434A>C
NM_000238.4:c.1900A>CMANE SELECT
NM_001204798.2:c.880A>C
NM_001406753.1:c.1612A>C
NM_001406755.1:c.1723A>C
NM_001406756.1:c.1612A>C
NM_001406757.1:c.1600A>C
NM_172056.3:c.1900A>C
NM_172057.3:c.880A>C
NP_000229.1:p.Thr634Pro
NP_000229.1:p.Thr634Pro
NP_001191727.1:p.Thr294Pro
NP_001393682.1:p.Thr538Pro
NP_001393684.1:p.Thr575Pro
NP_001393685.1:p.Thr538Pro
NP_001393686.1:p.Thr534Pro
NP_742053.1:p.Thr634Pro
NP_742053.1:p.Thr634Pro
NP_742054.1:p.Thr294Pro
NP_742054.1:p.Thr294Pro
LRG_288t1:c.1900A>C
LRG_288t2:c.1900A>C
LRG_288t3:c.880A>C
LRG_288:g.31434A>C
LRG_288p1:p.Thr634Pro
LRG_288p2:p.Thr634Pro
LRG_288p3:p.Thr294Pro
NC_000007.13:g.150648581T>G
NM_000238.3:c.1900A>C
NM_172056.2:c.1900A>C
NM_172057.2:c.880A>C
NR_176254.1:n.2308A>C
NR_176255.1:n.1181A>C

Protein change:

T294P

Molecular consequence:

NM_000238.4:c.1900A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.880A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1612A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1723A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1612A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1600A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1900A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.880A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Long QT syndrome 2 (LQT2)
Identifiers:: MONDO: MONDO:0013367; MedGen: C3150943; Orphanet: 101016; Orphanet: 768; OMIM: 613688

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002767758	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 19, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10753933, 19716085, 20301308, 21777565, 24363352, 27041096, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002767758

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 19, 2020)

germline

clinical testing

PubMed (7)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The dominant negative LQT2 mutation A561V reduces wild-type HERG expression.

Kagan A, Yu Z, Fishman GI, McDonald TV.

J Biol Chem. 2000 Apr 14;275(15):11241-8.

PubMed [citation]

PMID:: 10753933

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.

Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ.

Heart Rhythm. 2009 Sep;6(9):1297-303. doi: 10.1016/j.hrthm.2009.05.021. Epub 2009 Jun 23.

PubMed [citation]

PMID:: 19716085
PMCID:: PMC3049907

See all PubMed Citations (7)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767758.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3A - VUS. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with long QT syndrome (MIM#2613688). Gain of function is also a known mechanism associated with short QT syndrome (MIM#16096203) (OMIM, PMIDs: 10753933, 21777565). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to proline. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated S6 pore domain (PMID: 19716085). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Thr634Ile) and p.(Thr63Ala) missense variants have been reported in multiple individuals with long QT syndrome (ClinVar; PMIDs: 19716085, 27041096, 24363352). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Jun 9, 2024

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