NM_000218.3(KCNQ1):c.908T>C (p.Leu303Pro) AND Long QT syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 13, 2022
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:: RCV002513752.3

Allele description [Variation Report for NM_000218.3(KCNQ1):c.908T>C (p.Leu303Pro)]

NM_000218.3(KCNQ1):c.908T>C (p.Leu303Pro)

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.908T>C (p.Leu303Pro)

HGVS:

NC_000011.10:g.2572973T>C
NG_008935.1:g.132983T>C
NM_000218.3:c.908T>CMANE SELECT
NM_001406836.1:c.908T>C
NM_001406837.1:c.638T>C
NM_181798.2:c.527T>C
NP_000209.2:p.Leu303Pro
NP_000209.2:p.Leu303Pro
NP_001393765.1:p.Leu303Pro
NP_001393766.1:p.Leu213Pro
NP_861463.1:p.Leu176Pro
NP_861463.1:p.Leu176Pro
LRG_287t1:c.908T>C
LRG_287t2:c.527T>C
LRG_287:g.132983T>C
LRG_287p1:p.Leu303Pro
LRG_287p2:p.Leu176Pro
NC_000011.9:g.2594203T>C
NM_000218.2:c.908T>C
NM_181798.1:c.527T>C
NR_040711.2:n.801T>C
P51787:p.Leu303Pro

Protein change:

L176P

Links:

UniProtKB: P51787#VAR_074977; dbSNP: rs199472740

NCBI 1000 Genomes Browser:

rs199472740

Molecular consequence:

NM_000218.3:c.908T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.908T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.638T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.527T>C - 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
SCV003441567	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19716085, 26675252, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003441567

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 13, 2022)

germline

clinical testing

PubMed (3)
[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

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.

Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ.

Heart Rhythm. 2009 Sep;6(9):1297-303. doi: 10.1016/j.hrthm.2009.05.021. Epub 2009 Jun 23.

PubMed [citation]

PMID:: 19716085
PMCID:: PMC3049907

QT Adaptation and Intrinsic QT Variability in Congenital Long QT Syndrome.

Seethala S, Singh P, Shusterman V, Ribe M, Haugaa KH, Němec J.

J Am Heart Assoc. 2015 Dec 16;4(12). doi:pii: e002395. 10.1161/JAHA.115.002395.

PubMed [citation]

PMID:: 26675252
PMCID:: PMC4845278

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003441567.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 67122). This missense change has been observed in individual(s) with clinical features of autosomal dominant long QT Syndrome (PMID: 19716085, 26675252; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 303 of the KCNQ1 protein (p.Leu303Pro).

#	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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