NM_000238.4(KCNH2):c.1922C>T (p.Ser641Phe) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 30, 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:: RCV000803218.7

Allele description [Variation Report for NM_000238.4(KCNH2):c.1922C>T (p.Ser641Phe)]

NM_000238.4(KCNH2):c.1922C>T (p.Ser641Phe)

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.1922C>T (p.Ser641Phe)

HGVS:

NC_000007.14:g.150951471G>A
NG_008916.1:g.31456C>T
NM_000238.4:c.1922C>TMANE SELECT
NM_001204798.2:c.902C>T
NM_001406753.1:c.1634C>T
NM_001406755.1:c.1745C>T
NM_001406756.1:c.1634C>T
NM_001406757.1:c.1622C>T
NM_172056.3:c.1922C>T
NM_172057.3:c.902C>T
NP_000229.1:p.Ser641Phe
NP_000229.1:p.Ser641Phe
NP_001191727.1:p.Ser301Phe
NP_001393682.1:p.Ser545Phe
NP_001393684.1:p.Ser582Phe
NP_001393685.1:p.Ser545Phe
NP_001393686.1:p.Ser541Phe
NP_742053.1:p.Ser641Phe
NP_742053.1:p.Ser641Phe
NP_742054.1:p.Ser301Phe
NP_742054.1:p.Ser301Phe
LRG_288t1:c.1922C>T
LRG_288t2:c.1922C>T
LRG_288t3:c.902C>T
LRG_288:g.31456C>T
LRG_288p1:p.Ser641Phe
LRG_288p2:p.Ser641Phe
LRG_288p3:p.Ser301Phe
NC_000007.13:g.150648559G>A
NM_000238.3:c.1922C>T
NM_172056.2:c.1922C>T
NM_172057.2:c.902C>T
NR_176254.1:n.2330C>T
NR_176255.1:n.1203C>T
Q12809:p.Ser641Phe

Protein change:

S301F

Links:

UniProtKB: Q12809#VAR_068273; dbSNP: rs199472971

NCBI 1000 Genomes Browser:

rs199472971

Molecular consequence:

NM_000238.4:c.1922C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.902C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1634C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1745C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1634C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1622C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1922C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.902C>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
SCV000943080	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 30, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25417810, 22949429, 18441445, 21769575, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000943080

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 30, 2019)

germline

clinical testing

PubMed (5)
[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

Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.

Giudicessi JR, Kapplinger JD, Tester DJ, Alders M, Salisbury BA, Wilde AA, Ackerman MJ.

Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. doi: 10.1161/CIRCGENETICS.112.963785. Epub 2012 Sep 4.

PubMed [citation]

PMID:: 22949429
PMCID:: PMC3705705

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000943080.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect KCNH2 protein function (PMID: 25417810). This variant has been observed to be de novo in an individual affected with long QT syndrome (Invitae), and has been reported in other affected individuals (PMID: 22949429, 18441445, 21769575). ClinVar contains an entry for this variant (Variation ID: 67337). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with phenylalanine at codon 641 of the KCNH2 protein (p.Ser641Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine.

#	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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