NM_000238.4(KCNH2):c.1841C>T (p.Ala614Val) AND Long QT syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 21, 2022
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:: RCV000462085.11

Allele description [Variation Report for NM_000238.4(KCNH2):c.1841C>T (p.Ala614Val)]

NM_000238.4(KCNH2):c.1841C>T (p.Ala614Val)

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.1841C>T (p.Ala614Val)

HGVS:

NC_000007.14:g.150951552G>A
NG_008916.1:g.31375C>T
NM_000238.4:c.1841C>TMANE SELECT
NM_001204798.2:c.821C>T
NM_001406753.1:c.1553C>T
NM_001406755.1:c.1664C>T
NM_001406756.1:c.1553C>T
NM_001406757.1:c.1541C>T
NM_172056.3:c.1841C>T
NM_172057.3:c.821C>T
NP_000229.1:p.Ala614Val
NP_000229.1:p.Ala614Val
NP_001191727.1:p.Ala274Val
NP_001393682.1:p.Ala518Val
NP_001393684.1:p.Ala555Val
NP_001393685.1:p.Ala518Val
NP_001393686.1:p.Ala514Val
NP_742053.1:p.Ala614Val
NP_742053.1:p.Ala614Val
NP_742054.1:p.Ala274Val
NP_742054.1:p.Ala274Val
LRG_288t1:c.1841C>T
LRG_288t2:c.1841C>T
LRG_288t3:c.821C>T
LRG_288:g.31375C>T
LRG_288p1:p.Ala614Val
LRG_288p2:p.Ala614Val
LRG_288p3:p.Ala274Val
NC_000007.13:g.150648640G>A
NM_000238.2:c.1841C>T
NM_000238.3:c.1841C>T
NM_172056.2:c.1841C>T
NM_172057.2:c.821C>T
NR_176254.1:n.2249C>T
NR_176255.1:n.1122C>T
Q12809:p.Ala614Val

Protein change:

A274V; ALA614VAL

Links:

UniProtKB: Q12809#VAR_008931; OMIM: 152427.0026; dbSNP: rs199472944

NCBI 1000 Genomes Browser:

rs199472944

Molecular consequence:

NM_000238.4:c.1841C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.821C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1553C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1664C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1553C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1541C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1841C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.821C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000543482	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 21, 2022)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 16432067, 23303164, 25417810, 9024139, 9544837, 15090700, 18441445, 18808722, 19057127, 19996378, 22949429, 28492532
SCV000740337	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 30, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000917558	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 7, 2018)	germline	clinical testing	PubMed (24) [See all records that cite these PMIDs] 9721698, 18808722, 21960720, 21367833, 23303164, 9024139, 9693036, 19057127, 22949429, 18441445, 19843919, 19716085, 18752142, 15840476, 21295269, 21703926, 10560244, 21185501, 21240260, 19070294, 9544837, 9927399, 11854117, 10973849 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543482

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 21, 2022)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV000740337

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 30, 2016)

germline

clinical testing

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

SCV000917558

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 7, 2018)

germline

clinical testing

PubMed (24)
[See all records that cite these PMIDs]

Citation Link

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism.

Anderson CL, Delisle BP, Anson BD, Kilby JA, Will ML, Tester DJ, Gong Q, Zhou Z, Ackerman MJ, January CT.

Circulation. 2006 Jan 24;113(3):365-73.

PubMed [citation]

PMID:: 16432067

Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome.

Anderson CL, Kuzmicki CE, Childs RR, Hintz CJ, Delisle BP, January CT.

Nat Commun. 2014 Nov 24;5:5535. doi: 10.1038/ncomms6535.

PubMed [citation]

PMID:: 25417810
PMCID:: PMC4243539

See all PubMed Citations (30)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543482.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16432067, 19057127, 23303164, 25417810). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 29777). This missense change has been observed in individuals with long QT syndrome (PMID: 9024139, 9544837, 15090700, 18441445, 18808722, 19057127, 19996378, 22949429). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 614 of the KCNH2 protein (p.Ala614Val).

#	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

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000740337.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917558.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (24)

Description

Variant summary: KCNH2 c.1841C>T (p.Ala614Val) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250692 control chromosomes. c.1841C>T has been reported in the literature in numerous individuals affected with Long QT Syndrome. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, such as electrophysiological findings (Itzhaki_2011) and intracellular trafficking (Anderson_2006), both of which were impaired in the presence of the variant. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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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