NM_000238.4(KCNH2):c.1849T>C (p.Phe617Leu) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 6, 2019
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:: RCV000190214.10

Allele description [Variation Report for NM_000238.4(KCNH2):c.1849T>C (p.Phe617Leu)]

NM_000238.4(KCNH2):c.1849T>C (p.Phe617Leu)

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.1849T>C (p.Phe617Leu)

HGVS:

NC_000007.14:g.150951544A>G
NG_008916.1:g.31383T>C
NM_000238.4:c.1849T>CMANE SELECT
NM_001204798.2:c.829T>C
NM_001406753.1:c.1561T>C
NM_001406755.1:c.1672T>C
NM_001406756.1:c.1561T>C
NM_001406757.1:c.1549T>C
NM_172056.3:c.1849T>C
NM_172057.3:c.829T>C
NP_000229.1:p.Phe617Leu
NP_000229.1:p.Phe617Leu
NP_001191727.1:p.Phe277Leu
NP_001393682.1:p.Phe521Leu
NP_001393684.1:p.Phe558Leu
NP_001393685.1:p.Phe521Leu
NP_001393686.1:p.Phe517Leu
NP_742053.1:p.Phe617Leu
NP_742053.1:p.Phe617Leu
NP_742054.1:p.Phe277Leu
NP_742054.1:p.Phe277Leu
LRG_288t1:c.1849T>C
LRG_288t2:c.1849T>C
LRG_288t3:c.829T>C
LRG_288:g.31383T>C
LRG_288p1:p.Phe617Leu
LRG_288p2:p.Phe617Leu
LRG_288p3:p.Phe277Leu
NC_000007.13:g.150648632A>G
NM_000238.3:c.1849T>C
NM_172056.2:c.1849T>C
NM_172057.2:c.829T>C
NR_176254.1:n.2257T>C
NR_176255.1:n.1130T>C

Protein change:

F277L

Links:

dbSNP: rs796052195

NCBI 1000 Genomes Browser:

rs796052195

Molecular consequence:

NM_000238.4:c.1849T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.829T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1561T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1672T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1561T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1549T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1849T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.829T>C - 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
SCV000222065	Medical Research Institute, Tokyo Medical and Dental University See additional submitters Division of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo	no assertion criteria provided	Likely pathogenic	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001222713	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 6, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000222065

Medical Research Institute, Tokyo Medical and Dental University

See additional submitters

no assertion criteria provided

Likely pathogenic

germline

research

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

SCV001222713

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 6, 2019)

germline

clinical testing

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

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

Citations

PubMed

Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes.

Shigemizu D, Aiba T, Nakagawa H, Ozaki K, Miya F, Satake W, Toda T, Miyamoto Y, Fujimoto A, Suzuki Y, Kubo M, Tsunoda T, Shimizu W, Tanaka T.

PLoS One. 2015;10(7):e0130329. doi: 10.1371/journal.pone.0130329.

PubMed [citation]

PMID:: 26132555
PMCID:: PMC4488844

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 Medical Research Institute, Tokyo Medical and Dental University, SCV000222065.1

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

From Invitae, SCV001222713.5

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

Description

This variant is not present in population databases (ExAC no frequency). 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.Phe617 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID:¬†25987402), which suggests that this may be a clinically significant amino acid residue. 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"). This variant has been observed in individuals affected with clinical features of long QT syndrome (PMID:¬†26132555, Invitae). ClinVar contains an entry for this variant (Variation ID: 207940). This sequence change replaces phenylalanine with leucine at codon 617 of the KCNH2 protein (p.Phe617Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine.

#	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: Jun 23, 2024

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