NM_000238.4(KCNH2):c.652A>G (p.Met218Val) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 13, 2021
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:: RCV000690929.5

Allele description [Variation Report for NM_000238.4(KCNH2):c.652A>G (p.Met218Val)]

NM_000238.4(KCNH2):c.652A>G (p.Met218Val)

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.652A>G (p.Met218Val)

HGVS:

NC_000007.14:g.150958323T>C
NG_008916.1:g.24604A>G
NM_000238.4:c.652A>GMANE SELECT
NM_001406753.1:c.364A>G
NM_001406755.1:c.475A>G
NM_001406756.1:c.364A>G
NM_001406757.1:c.352A>G
NM_172056.3:c.652A>G
NP_000229.1:p.Met218Val
NP_000229.1:p.Met218Val
NP_001393682.1:p.Met122Val
NP_001393684.1:p.Met159Val
NP_001393685.1:p.Met122Val
NP_001393686.1:p.Met118Val
NP_742053.1:p.Met218Val
NP_742053.1:p.Met218Val
LRG_288t1:c.652A>G
LRG_288t2:c.652A>G
LRG_288:g.24604A>G
LRG_288p1:p.Met218Val
LRG_288p2:p.Met218Val
NC_000007.13:g.150655411T>C
NM_000238.2:c.652A>G
NM_000238.3:c.652A>G
NM_172056.2:c.652A>G
NR_176254.1:n.1060A>G
Q12809:p.Met218Val

Protein change:

M118V

Links:

UniProtKB: Q12809#VAR_074799; dbSNP: rs199472869

NCBI 1000 Genomes Browser:

rs199472869

Molecular consequence:

NM_000238.4:c.652A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.364A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.364A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.352A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.652A>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
SCV000818660	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 13, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19716085, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000818660

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 13, 2021)

germline

clinical testing

PubMed (2)
[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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000818660.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces methionine with valine at codon 218 of the KCNH2 protein (p.Met218Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67516). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

#	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: Oct 8, 2024

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