NM_000238.4(KCNH2):c.656A>T (p.Asp219Val) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 8, 2024
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:: RCV001234187.10

Allele description [Variation Report for NM_000238.4(KCNH2):c.656A>T (p.Asp219Val)]

NM_000238.4(KCNH2):c.656A>T (p.Asp219Val)

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.656A>T (p.Asp219Val)

HGVS:

NC_000007.14:g.150958319T>A
NG_008916.1:g.24608A>T
NM_000238.4:c.656A>TMANE SELECT
NM_001406753.1:c.368A>T
NM_001406755.1:c.479A>T
NM_001406756.1:c.368A>T
NM_001406757.1:c.356A>T
NM_172056.3:c.656A>T
NP_000229.1:p.Asp219Val
NP_000229.1:p.Asp219Val
NP_001393682.1:p.Asp123Val
NP_001393684.1:p.Asp160Val
NP_001393685.1:p.Asp123Val
NP_001393686.1:p.Asp119Val
NP_742053.1:p.Asp219Val
NP_742053.1:p.Asp219Val
LRG_288t1:c.656A>T
LRG_288t2:c.656A>T
LRG_288:g.24608A>T
LRG_288p1:p.Asp219Val
LRG_288p2:p.Asp219Val
NC_000007.13:g.150655407T>A
NM_000238.3:c.656A>T
NM_172056.2:c.656A>T
NR_176254.1:n.1064A>T

Protein change:

D119V

Links:

dbSNP: rs587777907

NCBI 1000 Genomes Browser:

rs587777907

Molecular consequence:

NM_000238.4:c.656A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.368A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.479A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.368A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.356A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.656A>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
SCV001406819	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25914329, 28492532
SCV004022001	Dept of Medical Biology, Uskudar University	criteria provided, single submitter (Dept of Medical Biology Variant Classification)	Uncertain significance (Jan 8, 2024)	unknown	research	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001406819

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 13, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004022001

Dept of Medical Biology, Uskudar University

criteria provided, single submitter

(Dept of Medical Biology Variant Classification)

Uncertain significance
(Jan 8, 2024)

unknown

research

Citation Link

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
Turkish	unknown	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

An Interdomain KCNH2 Mutation Produces an Intermediate Long QT Syndrome.

Osterbur ML, Zheng R, Marion R, Walsh C, McDonald TV.

Hum Mutat. 2015 Aug;36(8):764-73. doi: 10.1002/humu.22805. Epub 2015 Jun 13. Erratum in: Hum Mutat. 2019 Mar;40(3):357. doi: 10.1002/humu.23711.

PubMed [citation]

PMID:: 25914329
PMCID:: PMC4667707

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, SCV001406819.4

#	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 aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 219 of the KCNH2 protein (p.Asp219Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with long QT syndrome (PMID: 25914329). ClinVar contains an entry for this variant (Variation ID: 157662). 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: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25914329). 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

From Dept of Medical Biology, Uskudar University, SCV004022001.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Turkish	1	not provided	not provided	research	not provided

Description

Criteria: PM2, PP2

#	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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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