NM_000238.4(KCNH2):c.1814C>T (p.Pro605Leu) AND Long QT syndrome 2

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 19, 2020
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:: RCV000735254.4

Allele description [Variation Report for NM_000238.4(KCNH2):c.1814C>T (p.Pro605Leu)]

NM_000238.4(KCNH2):c.1814C>T (p.Pro605Leu)

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.1814C>T (p.Pro605Leu)

HGVS:

NC_000007.14:g.150951579G>A
NG_008916.1:g.31348C>T
NM_000238.4:c.1814C>TMANE SELECT
NM_001204798.2:c.794C>T
NM_001406753.1:c.1526C>T
NM_001406755.1:c.1637C>T
NM_001406756.1:c.1526C>T
NM_001406757.1:c.1514C>T
NM_172056.3:c.1814C>T
NM_172057.3:c.794C>T
NP_000229.1:p.Pro605Leu
NP_000229.1:p.Pro605Leu
NP_001191727.1:p.Pro265Leu
NP_001393682.1:p.Pro509Leu
NP_001393684.1:p.Pro546Leu
NP_001393685.1:p.Pro509Leu
NP_001393686.1:p.Pro505Leu
NP_742053.1:p.Pro605Leu
NP_742053.1:p.Pro605Leu
NP_742054.1:p.Pro265Leu
NP_742054.1:p.Pro265Leu
LRG_288t1:c.1814C>T
LRG_288t2:c.1814C>T
LRG_288t3:c.794C>T
LRG_288:g.31348C>T
LRG_288p1:p.Pro605Leu
LRG_288p2:p.Pro605Leu
LRG_288p3:p.Pro265Leu
NC_000007.13:g.150648667G>A
NM_000238.3:c.1814C>T
NM_172056.2:c.1814C>T
NM_172057.2:c.794C>T
NR_176254.1:n.2222C>T
NR_176255.1:n.1095C>T
Q12809:p.Pro605Leu

Protein change:

P265L

Links:

UniProtKB: Q12809#VAR_074844; dbSNP: rs199472938

NCBI 1000 Genomes Browser:

rs199472938

Molecular consequence:

NM_000238.4:c.1814C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.794C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1526C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1637C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1526C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1514C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1814C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.794C>T - 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

Recent activity

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Chain F, Mitochondrial import receptor subunit TOM7 homolog
Chain F, Mitochondrial import receptor subunit TOM7 homolog
gi|2030911257|pdb|7CP9|F

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000863463	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 11, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002767863	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 19, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10753933, 19716085, 20301308, 21777565, 21956039, 25417810, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000863463

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 11, 2018)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002767863

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	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 Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues, SCV000863463.1

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

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767863.1

#	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 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 (PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (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 pore region (PMID: 21956039). (I) 0704 - Another two missense variants comparable to the one identified in this case has limited previous evidence for pathogenicity. A different amino acid change to serine at the same position has been reported in a patient with Long QT syndrome 2 (ClinVar, PMID: 19716085). Additionally another change to histidine at the same position has been reported as VUS in ClinVar. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with Long QT syndrome (ClinVar, PMID: 19716085, 21956039). (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 studies using HEK293 cells show that this variant leads to deficient trafficking (PMID: 25417810). (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: Jun 9, 2024

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