NM_000238.4(KCNH2):c.2414T>G (p.Phe805Cys) AND Long QT syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 25, 2016
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:: RCV000474113.14

Allele description [Variation Report for NM_000238.4(KCNH2):c.2414T>G (p.Phe805Cys)]

NM_000238.4(KCNH2):c.2414T>G (p.Phe805Cys)

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.2414T>G (p.Phe805Cys)

Other names:

p.F805C:TTT>TGT

HGVS:

NC_000007.14:g.150949034A>C
NG_008916.1:g.33893T>G
NG_112814.1:g.250A>C
NM_000238.4:c.2414T>GMANE SELECT
NM_001406753.1:c.2126T>G
NM_172057.3:c.1394T>G
NP_000229.1:p.Phe805Cys
NP_000229.1:p.Phe805Cys
NP_001393682.1:p.Phe709Cys
NP_742054.1:p.Phe465Cys
NP_742054.1:p.Phe465Cys
LRG_288t1:c.2414T>G
LRG_288t3:c.1394T>G
LRG_288:g.33893T>G
LRG_288p1:p.Phe805Cys
LRG_288p3:p.Phe465Cys
NC_000007.13:g.150646122A>C
NM_000238.2:c.2414T>G
NM_000238.3:c.2414T>G
NM_172056.1:c.*865T>G
NM_172057.2:c.1394T>G
NR_176254.1:n.2822T>G
NR_176255.1:n.1695T>G
Q12809:p.Phe805Cys

Protein change:

F465C

Links:

UniProtKB: Q12809#VAR_014384; dbSNP: rs199472999

NCBI 1000 Genomes Browser:

rs199472999

Molecular consequence:

NM_000238.4:c.2414T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.2126T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1394T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_176254.1:n.2822T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176255.1:n.1695T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000543449	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 25, 2016)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19841300, 16432067, 23303164, 11741928, 12837749, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543449

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 25, 2016)

germline

clinical testing

PubMed (6)
[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

Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.

Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ.

Circulation. 2009 Nov 3;120(18):1752-60. doi: 10.1161/CIRCULATIONAHA.109.863076. Epub 2009 Oct 19.

PubMed [citation]

PMID:: 19841300
PMCID:: PMC3025752

Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism.

Anderson CL, Delisle BP, Anson BD, Kilby JA, Will ML, Tester DJ, Gong Q, Zhou Z, Ackerman MJ, January CT.

Circulation. 2006 Jan 24;113(3):365-73.

PubMed [citation]

PMID:: 16432067

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543449.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Likely Pathogenic. This variant identified in the KCNH2 gene is located in the cytoplasmic cyclic nucleotide binding region of the resulting protein (PMID: 19841300). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. Experimental studies have shown that this variant affects protein trafficking and therefore potassium channel current (PMID: 16432067, 23303164, 11741928, 12837749) This variant has been reported in a family affected with long QT syndrome (PMID:¬†11854117). ClinVar contains an entry for this variant (Variation ID: 67397). This variant is not present in population databases (rs199472999, ExAC no frequency). This sequence change replaces phenylalanine with cysteine at codon 805 of the KCNH2 protein (p.Phe805Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine.

#	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: Nov 10, 2024

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