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NM_000218.3(KCNQ1):c.899C>A (p.Ala300Glu) AND Long QT syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 11, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000470657.9

Allele description [Variation Report for NM_000218.3(KCNQ1):c.899C>A (p.Ala300Glu)]

NM_000218.3(KCNQ1):c.899C>A (p.Ala300Glu)

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.899C>A (p.Ala300Glu)
HGVS:
  • NC_000011.10:g.2572964C>A
  • NG_008935.1:g.132974C>A
  • NM_000218.3:c.899C>AMANE SELECT
  • NM_001406836.1:c.899C>A
  • NM_001406837.1:c.629C>A
  • NM_181798.2:c.518C>A
  • NP_000209.2:p.Ala300Glu
  • NP_000209.2:p.Ala300Glu
  • NP_001393765.1:p.Ala300Glu
  • NP_001393766.1:p.Ala210Glu
  • NP_861463.1:p.Ala173Glu
  • NP_861463.1:p.Ala173Glu
  • LRG_287t1:c.899C>A
  • LRG_287t2:c.518C>A
  • LRG_287:g.132974C>A
  • LRG_287p1:p.Ala300Glu
  • LRG_287p2:p.Ala173Glu
  • NC_000011.9:g.2594194C>A
  • NM_000218.2:c.899C>A
  • NM_181798.1:c.518C>A
  • NR_040711.2:n.792C>A
Protein change:
A173E
Links:
dbSNP: rs1001293702
NCBI 1000 Genomes Browser:
rs1001293702
Molecular consequence:
  • NM_000218.3:c.899C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406836.1:c.899C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406837.1:c.629C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.2:c.518C>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Long QT syndrome (LQTS)
Identifiers:
MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000543300Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Feb 6, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004842601All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Jan 11, 2024) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

A recessive variant of the Romano-Ward long-QT syndrome?

Priori SG, Schwartz PJ, Napolitano C, Bianchi L, Dennis A, De Fusco M, Brown AM, Casari G.

Circulation. 1998 Jun 23;97(24):2420-5.

PubMed [citation]
PMID:
9641694

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 (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543300.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 300 of the KCNQ1 protein (p.Ala300Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 405257). 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. This variant disrupts the p.Ala300 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 9641694, 11087258, 27251404, 28600177, 30571187, 33693037; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004842601.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024