NM_000238.4(KCNH2):c.1843C>G (p.Leu615Val) AND Long QT syndrome 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 2, 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:: RCV002470744.1

Allele description [Variation Report for NM_000238.4(KCNH2):c.1843C>G (p.Leu615Val)]

NM_000238.4(KCNH2):c.1843C>G (p.Leu615Val)

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.1843C>G (p.Leu615Val)

HGVS:

NC_000007.14:g.150951550G>C
NG_008916.1:g.31377C>G
NM_000238.4:c.1843C>GMANE SELECT
NM_001204798.2:c.823C>G
NM_001406753.1:c.1555C>G
NM_001406755.1:c.1666C>G
NM_001406756.1:c.1555C>G
NM_001406757.1:c.1543C>G
NM_172056.3:c.1843C>G
NM_172057.3:c.823C>G
NP_000229.1:p.Leu615Val
NP_000229.1:p.Leu615Val
NP_001191727.1:p.Leu275Val
NP_001393682.1:p.Leu519Val
NP_001393684.1:p.Leu556Val
NP_001393685.1:p.Leu519Val
NP_001393686.1:p.Leu515Val
NP_742053.1:p.Leu615Val
NP_742053.1:p.Leu615Val
NP_742054.1:p.Leu275Val
NP_742054.1:p.Leu275Val
LRG_288t1:c.1843C>G
LRG_288t2:c.1843C>G
LRG_288t3:c.823C>G
LRG_288:g.31377C>G
LRG_288p1:p.Leu615Val
LRG_288p2:p.Leu615Val
LRG_288p3:p.Leu275Val
NC_000007.13:g.150648638G>C
NM_000238.3:c.1843C>G
NM_172056.2:c.1843C>G
NM_172057.2:c.823C>G
NR_176254.1:n.2251C>G
NR_176255.1:n.1124C>G
Q12809:p.Leu615Val

Protein change:

L275V

Links:

UniProtKB: Q12809#VAR_014375; dbSNP: rs199472945

NCBI 1000 Genomes Browser:

rs199472945

Molecular consequence:

NM_000238.4:c.1843C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.823C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1555C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1666C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1555C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1543C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1843C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.823C>G - 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
SCV002769075	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10753933, 10973849, 11524404, 16414944, 21777565, 25417810, 26669661, 31557540, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002769075

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 2, 2022)

germline

clinical testing

PubMed (9)
[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 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

See all PubMed Citations (9)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769075.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. 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 2 (MIM#613688). Gain of function is also a known mechanism associated with short QT syndrome 1 (MIM#609620) (OMIM, PMID: 10753933; PMID: 21777565). (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 leucine to valine. (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 and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated ion-transport pore helix domain (DECIPHER, PMID: 11524404). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Leu615Phe) variant has been reported in three individuals or families with long QT syndrome or Romano-Ward syndrome (ClinVar, PMIDs: 16414944, 26669661). Additionally, functional studies have demonstrated that this variant results in abnormal trafficking and severely reduced protein expression and peak tail current compared to WT (PMIDs: 25417810, 31557540). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported once in a family with Romano-Ward syndrome (PMID: 10973849). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs expressed in Xenopus oocytes demonstrated reduced protein channel expression and induced very small peak currents compared to WT. Moreover, the mutant construct demonstrated dominant-negative effects when co-expressed with WT in Xenopus oocytes (PMID: 11524404). (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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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