NM_000218.3(KCNQ1):c.944A>T (p.Tyr315Phe) AND Long QT syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 15, 2023
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:: RCV003531946.1

Allele description [Variation Report for NM_000218.3(KCNQ1):c.944A>T (p.Tyr315Phe)]

NM_000218.3(KCNQ1):c.944A>T (p.Tyr315Phe)

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.944A>T (p.Tyr315Phe)

HGVS:

NC_000011.10:g.2583457A>T
NG_008935.1:g.143467A>T
NM_000218.3:c.944A>TMANE SELECT
NM_001406836.1:c.944A>T
NM_001406837.1:c.674A>T
NM_001406838.1:c.500A>T
NM_181798.2:c.563A>T
NP_000209.2:p.Tyr315Phe
NP_000209.2:p.Tyr315Phe
NP_001393765.1:p.Tyr315Phe
NP_001393766.1:p.Tyr225Phe
NP_001393767.1:p.Tyr167Phe
NP_861463.1:p.Tyr188Phe
NP_861463.1:p.Tyr188Phe
LRG_287t1:c.944A>T
LRG_287t2:c.563A>T
LRG_287:g.143467A>T
LRG_287p1:p.Tyr315Phe
LRG_287p2:p.Tyr188Phe
NC_000011.9:g.2604687A>T
NM_000218.2:c.944A>T
NM_181798.1:c.563A>T
NR_040711.2:n.837A>T

Protein change:

Y167F

Links:

dbSNP: rs74462309

NCBI 1000 Genomes Browser:

rs74462309

Molecular consequence:

NM_000218.3:c.944A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.944A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.674A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.500A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.563A>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
SCV004294070	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 15, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19841300, 11087258, 12702160, 18774102, 21451124, 24217263, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004294070

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 15, 2023)

germline

clinical testing

PubMed (7)
[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

Mechanisms of I(Ks) suppression in LQT1 mutants.

Bianchi L, Priori SG, Napolitano C, Surewicz KA, Dennis AT, Memmi M, Schwartz PJ, Brown AM.

Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H3003-11.

PubMed [citation]

PMID:: 11087258

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV004294070.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 315 of the KCNQ1 protein (p.Tyr315Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 19841300). ClinVar contains an entry for this variant (Variation ID: 53141). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. This variant disrupts the p.Tyr315 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11087258, 12702160, 18774102, 21451124, 24217263). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Feb 20, 2024

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