NM_000238.4(KCNH2):c.2131A>G (p.Ile711Val) AND Long QT syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 13, 2023
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:: RCV000148537.17

Allele description [Variation Report for NM_000238.4(KCNH2):c.2131A>G (p.Ile711Val)]

NM_000238.4(KCNH2):c.2131A>G (p.Ile711Val)

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.2131A>G (p.Ile711Val)

Other names:

p.I711V:ATC>GTC

HGVS:

NC_000007.14:g.150950935T>C
NG_008916.1:g.31992A>G
NM_000238.4:c.2131A>GMANE SELECT
NM_001204798.2:c.1111A>G
NM_001406753.1:c.1843A>G
NM_001406755.1:c.1954A>G
NM_001406756.1:c.1843A>G
NM_001406757.1:c.1831A>G
NM_172056.3:c.2131A>G
NM_172057.3:c.1111A>G
NP_000229.1:p.Ile711Val
NP_000229.1:p.Ile711Val
NP_001191727.1:p.Ile371Val
NP_001393682.1:p.Ile615Val
NP_001393684.1:p.Ile652Val
NP_001393685.1:p.Ile615Val
NP_001393686.1:p.Ile611Val
NP_742053.1:p.Ile711Val
NP_742053.1:p.Ile711Val
NP_742054.1:p.Ile371Val
NP_742054.1:p.Ile371Val
LRG_288t1:c.2131A>G
LRG_288t2:c.2131A>G
LRG_288t3:c.1111A>G
LRG_288:g.31992A>G
LRG_288p1:p.Ile711Val
LRG_288p2:p.Ile711Val
LRG_288p3:p.Ile371Val
NC_000007.13:g.150648023T>C
NM_000238.2:c.2131A>G
NM_000238.3:c.2131A>G
NM_172056.2:c.2131A>G
NM_172057.2:c.1111A>G
NR_176254.1:n.2539A>G
NR_176255.1:n.1412A>G
Q12809:p.Ile711Val

Protein change:

I371V

Links:

UniProtKB: Q12809#VAR_074871; dbSNP: rs199473532

NCBI 1000 Genomes Browser:

rs199473532

Molecular consequence:

NM_000238.4:c.2131A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.1111A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1843A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1954A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1843A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1831A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.2131A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1111A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000190250	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV001408834	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 30, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19716085, 26746457, 25417810, 28492532
SCV004843928	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25417810, 26746457, 27807201, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190250

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Uncertain significance
(Jun 1, 2014)

germline

research

SCV001408834

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 30, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004843928

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 2023)

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	9	not provided	not provided	108544	not provided	clinical testing, research

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

See all PubMed Citations (6)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190250.1

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001408834.4

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 711 of the KCNH2 protein (p.Ile711Val). This variant is present in population databases (rs199473532, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085, 26746457). ClinVar contains an entry for this variant (Variation ID: 67367). 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 disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810). 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 All of Us Research Program, National Institutes of Health, SCV004843928.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces isoleucine with valine at codon 711 of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Functional studies have shown that this variant may affect channel gating (PMID: 25417810, 27807201). However, clinical relevance of this observation is not clear. This variant has been reported in an individuals affected with long QT syndrome (PMID: 26746457). This variant has also been identified in 9/251380 chromosomes (8/10080 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		9	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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