NM_000218.3(KCNQ1):c.959C>A (p.Pro320His) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 26, 2018
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:: RCV001387950.7

Allele description [Variation Report for NM_000218.3(KCNQ1):c.959C>A (p.Pro320His)]

NM_000218.3(KCNQ1):c.959C>A (p.Pro320His)

Gene:

KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000218.3(KCNQ1):c.959C>A (p.Pro320His)

HGVS:

NC_000011.10:g.2583472C>A
NG_008935.1:g.143482C>A
NM_000218.3:c.959C>AMANE SELECT
NM_001406836.1:c.959C>A
NM_001406837.1:c.689C>A
NM_001406838.1:c.515C>A
NM_181798.2:c.578C>A
NP_000209.2:p.Pro320His
NP_000209.2:p.Pro320His
NP_001393765.1:p.Pro320His
NP_001393766.1:p.Pro230His
NP_001393767.1:p.Pro172His
NP_861463.1:p.Pro193His
NP_861463.1:p.Pro193His
LRG_287t1:c.959C>A
LRG_287t2:c.578C>A
LRG_287:g.143482C>A
LRG_287p1:p.Pro320His
LRG_287p2:p.Pro193His
NC_000011.9:g.2604702C>A
NM_000218.2:c.959C>A
NM_181798.1:c.578C>A
NR_040711.2:n.852C>A
P51787:p.Pro320His

Protein change:

P172H

Links:

UniProtKB: P51787#VAR_065778; dbSNP: rs199473470

NCBI 1000 Genomes Browser:

rs199473470

Molecular consequence:

NM_000218.3:c.959C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.959C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.689C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.515C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.578C>A - 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
SCV001588721	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 26, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22949429, 19540844, 9386136, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001588721

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 26, 2018)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Biophysical characterization of KCNQ1 P320 mutations linked to long QT syndrome 1.

Thomas D, Khalil M, Alter M, Schweizer PA, Karle CA, Wimmer AB, Licka M, Katus HA, Koenen M, Ulmer HE, Zehelein J.

J Mol Cell Cardiol. 2010 Jan;48(1):230-7. doi: 10.1016/j.yjmcc.2009.06.009. Epub 2009 Jun 21.

PubMed [citation]

PMID:: 19540844

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001588721.4

#	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 proline with histidine at codon 320 of the KCNQ1 protein (p.Pro320His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with long QT syndrome (PMID: 22949429, 19540844,¬†17470695, Invitae). ClinVar contains an entry for this variant (Variation ID: 53148). Experimental studies have shown that this missense change results in a non-functional sodium channel (PMID:¬†19540844). This variant disrupts the p.Pro320 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 9386136,¬† Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

#	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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