NM_000238.4(KCNH2):c.1814C>T (p.Pro605Leu) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 24, 2017
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:: RCV000631723.6

Allele description [Variation Report for NM_000238.4(KCNH2):c.1814C>T (p.Pro605Leu)]

NM_000238.4(KCNH2):c.1814C>T (p.Pro605Leu)

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.1814C>T (p.Pro605Leu)

HGVS:

NC_000007.14:g.150951579G>A
NG_008916.1:g.31348C>T
NM_000238.4:c.1814C>TMANE SELECT
NM_001204798.2:c.794C>T
NM_001406753.1:c.1526C>T
NM_001406755.1:c.1637C>T
NM_001406756.1:c.1526C>T
NM_001406757.1:c.1514C>T
NM_172056.3:c.1814C>T
NM_172057.3:c.794C>T
NP_000229.1:p.Pro605Leu
NP_000229.1:p.Pro605Leu
NP_001191727.1:p.Pro265Leu
NP_001393682.1:p.Pro509Leu
NP_001393684.1:p.Pro546Leu
NP_001393685.1:p.Pro509Leu
NP_001393686.1:p.Pro505Leu
NP_742053.1:p.Pro605Leu
NP_742053.1:p.Pro605Leu
NP_742054.1:p.Pro265Leu
NP_742054.1:p.Pro265Leu
LRG_288t1:c.1814C>T
LRG_288t2:c.1814C>T
LRG_288t3:c.794C>T
LRG_288:g.31348C>T
LRG_288p1:p.Pro605Leu
LRG_288p2:p.Pro605Leu
LRG_288p3:p.Pro265Leu
NC_000007.13:g.150648667G>A
NM_000238.3:c.1814C>T
NM_172056.2:c.1814C>T
NM_172057.2:c.794C>T
NR_176254.1:n.2222C>T
NR_176255.1:n.1095C>T
Q12809:p.Pro605Leu

Protein change:

P265L

Links:

UniProtKB: Q12809#VAR_074844; dbSNP: rs199472938

NCBI 1000 Genomes Browser:

rs199472938

Molecular consequence:

NM_000238.4:c.1814C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.794C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1526C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1637C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1526C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1514C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1814C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.794C>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
SCV000752811	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 24, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25417810, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000752811

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 24, 2017)

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

Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome.

Anderson CL, Kuzmicki CE, Childs RR, Hintz CJ, Delisle BP, January CT.

Nat Commun. 2014 Nov 24;5:5535. doi: 10.1038/ncomms6535.

PubMed [citation]

PMID:: 25417810
PMCID:: PMC4243539

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, SCV000752811.4

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

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. Experimental studies have shown that this missense change causes the KCNH2 protein to be trafficking-deficient (PMID: 25417810). This variant has not been reported in the literature in individuals with KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 67284). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 605 of the KCNH2 protein (p.Pro605Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline 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: Sep 29, 2024

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