NM_000238.4(KCNH2):c.1779A>G (p.Ile593Met) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 6, 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:: RCV002979177.3

Allele description [Variation Report for NM_000238.4(KCNH2):c.1779A>G (p.Ile593Met)]

NM_000238.4(KCNH2):c.1779A>G (p.Ile593Met)

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.1779A>G (p.Ile593Met)

HGVS:

NC_000007.14:g.150951614T>C
NG_008916.1:g.31313A>G
NM_000238.4:c.1779A>GMANE SELECT
NM_001204798.2:c.759A>G
NM_001406753.1:c.1491A>G
NM_001406755.1:c.1602A>G
NM_001406756.1:c.1491A>G
NM_001406757.1:c.1479A>G
NM_172056.3:c.1779A>G
NM_172057.3:c.759A>G
NP_000229.1:p.Ile593Met
NP_000229.1:p.Ile593Met
NP_001191727.1:p.Ile253Met
NP_001393682.1:p.Ile497Met
NP_001393684.1:p.Ile534Met
NP_001393685.1:p.Ile497Met
NP_001393686.1:p.Ile493Met
NP_742053.1:p.Ile593Met
NP_742053.1:p.Ile593Met
NP_742054.1:p.Ile253Met
NP_742054.1:p.Ile253Met
LRG_288t1:c.1779A>G
LRG_288t2:c.1779A>G
LRG_288t3:c.759A>G
LRG_288:g.31313A>G
LRG_288p1:p.Ile593Met
LRG_288p2:p.Ile593Met
LRG_288p3:p.Ile253Met
NC_000007.13:g.150648702T>C
NM_000238.3:c.1779A>G
NM_172056.2:c.1779A>G
NM_172057.2:c.759A>G
NR_176254.1:n.2187A>G
NR_176255.1:n.1060A>G

Protein change:

I253M

Molecular consequence:

NM_000238.4:c.1779A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.759A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1491A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1602A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1491A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1479A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1779A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.759A>G - 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
SCV003287852	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 6, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8635257, 19716085, 21956039, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003287852

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 6, 2022)

germline

clinical testing

PubMed (4)
[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

Missense mutation in the pore region of HERG causes familial long QT syndrome.

Benson DW, MacRae CA, Vesely MR, Walsh EP, Seidman JG, Seidman CE, Satler CA.

Circulation. 1996 May 15;93(10):1791-5.

PubMed [citation]

PMID:: 8635257

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 (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003287852.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ile593 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8635257, 19716085, 21956039; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with clinical features of long QT syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 593 of the KCNH2 protein (p.Ile593Met).

#	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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