NM_000238.4(KCNH2):c.1888G>C (p.Val630Leu) AND Long QT syndrome 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 2, 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:: RCV002470745.2

Allele description [Variation Report for NM_000238.4(KCNH2):c.1888G>C (p.Val630Leu)]

NM_000238.4(KCNH2):c.1888G>C (p.Val630Leu)

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.1888G>C (p.Val630Leu)

HGVS:

NC_000007.14:g.150951505C>G
NG_008916.1:g.31422G>C
NM_000238.4:c.1888G>CMANE SELECT
NM_001204798.2:c.868G>C
NM_001406753.1:c.1600G>C
NM_001406755.1:c.1711G>C
NM_001406756.1:c.1600G>C
NM_001406757.1:c.1588G>C
NM_172056.3:c.1888G>C
NM_172057.3:c.868G>C
NP_000229.1:p.Val630Leu
NP_000229.1:p.Val630Leu
NP_001191727.1:p.Val290Leu
NP_001393682.1:p.Val534Leu
NP_001393684.1:p.Val571Leu
NP_001393685.1:p.Val534Leu
NP_001393686.1:p.Val530Leu
NP_742053.1:p.Val630Leu
NP_742053.1:p.Val630Leu
NP_742054.1:p.Val290Leu
NP_742054.1:p.Val290Leu
LRG_288t1:c.1888G>C
LRG_288t2:c.1888G>C
LRG_288t3:c.868G>C
LRG_288:g.31422G>C
LRG_288p1:p.Val630Leu
LRG_288p2:p.Val630Leu
LRG_288p3:p.Val290Leu
NC_000007.13:g.150648593C>G
NM_000238.3:c.1888G>C
NM_172056.2:c.1888G>C
NM_172057.2:c.868G>C
NR_176254.1:n.2296G>C
NR_176255.1:n.1169G>C
Q12809:p.Val630Leu

Protein change:

V290L

Links:

UniProtKB: Q12809#VAR_008934; dbSNP: rs199472958

NCBI 1000 Genomes Browser:

rs199472958

Molecular consequence:

NM_000238.4:c.1888G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.868G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1600G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1711G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1600G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1588G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1888G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.868G>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
SCV002766607	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 2, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9024139, 9693036, 9721698, 15840476, 28449774, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002766607

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 2, 2020)

germline

clinical testing

PubMed (6)
[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

Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.

Tanaka T, Nagai R, Tomoike H, Takata S, Yano K, Yabuta K, Haneda N, Nakano O, Shibata A, Sawayama T, Kasai H, Yazaki Y, Nakamura Y.

Circulation. 1997 Feb 4;95(3):565-7.

PubMed [citation]

PMID:: 9024139

Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1.

Splawski I, Shen J, Timothy KW, Vincent GM, Lehmann MH, Keating MT.

Genomics. 1998 Jul 1;51(1):86-97.

PubMed [citation]

PMID:: 9693036

See all PubMed Citations (6)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766607.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with long QT syndrome type 2. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Highly conserved, minor amino acid change. (SP) 0600 - Variant is located in the annotated pore domain (PDB). (I) 0703 – Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Val630Ile) has two likely pathogenic entries in ClinVar and has been classified as pathogenic in a sudden arrhythmic death patient (PMID: 28449774). p.(Val630Ala) has been reported in two LQTS patients, one being de novo (PMID: 15840476, 9693036). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individuals. This variant has been identified in a Japanese LQTS patient (PMID: 9024139) and has one ClinVar entry (no classification provided). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional evidence shows that this variant decreases slope conductance and negatively shifts steady-state inactivation (PMID: 9721698). (SP) 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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