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NM_000218.3(KCNQ1):c.521G>C (p.Arg174Pro) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 10, 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:
RCV003162398.2

Allele description [Variation Report for NM_000218.3(KCNQ1):c.521G>C (p.Arg174Pro)]

NM_000218.3(KCNQ1):c.521G>C (p.Arg174Pro)

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.521G>C (p.Arg174Pro)
HGVS:
  • NC_000011.10:g.2570671G>C
  • NG_008935.1:g.130681G>C
  • NM_000218.3:c.521G>CMANE SELECT
  • NM_001406836.1:c.521G>C
  • NM_001406837.1:c.251G>C
  • NM_181798.2:c.140G>C
  • NP_000209.2:p.Arg174Pro
  • NP_000209.2:p.Arg174Pro
  • NP_001393765.1:p.Arg174Pro
  • NP_001393766.1:p.Arg84Pro
  • NP_861463.1:p.Arg47Pro
  • NP_861463.1:p.Arg47Pro
  • LRG_287t1:c.521G>C
  • LRG_287t2:c.140G>C
  • LRG_287:g.130681G>C
  • LRG_287p1:p.Arg174Pro
  • LRG_287p2:p.Arg47Pro
  • NC_000011.9:g.2591901G>C
  • NM_000218.2:c.521G>C
  • NM_181798.1:c.140G>C
  • NR_040711.2:n.414G>C
  • P51787:p.Arg174Pro
Protein change:
R174P
Links:
UniProtKB: P51787#VAR_074942; dbSNP: rs199472697
NCBI 1000 Genomes Browser:
rs199472697
Molecular consequence:
  • NM_000218.3:c.521G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406836.1:c.521G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406837.1:c.251G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.2:c.140G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003900270Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Nov 10, 2022) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region.

Schwartz PJ, Moreno C, Kotta MC, Pedrazzini M, Crotti L, Dagradi F, Castelletti S, Haugaa KH, Denjoy I, Shkolnikova MA, Brink PA, Heradien MJ, Seyen SRM, Spätjens RLHMG, Spazzolini C, Volders PGA.

Eur Heart J. 2021 Dec 7;42(46):4743-4755. doi: 10.1093/eurheartj/ehab582.

PubMed [citation]
PMID:
34505893
PMCID:
PMC8851466

Details of each submission

From Ambry Genetics, SCV003900270.2

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

Description

The p.R174P variant (also known as c.521G>C), located in coding exon 3 of the KCNQ1 gene, results from a G to C substitution at nucleotide position 521. The arginine at codon 174 is replaced by proline, an amino acid with dissimilar properties. This variant has been detected in individuals from long QT syndrome (LQTS) cohorts or with QTc intervals consistent with LQTS (Napolitano C et al. JAMA. 2005 Dec;294(23):2975-80; Schwartz PJ et al. Eur Heart J. 2021 12;42:4743-4755; Ambry internal data). Another alteration at the same codon, p.R174H (c.521G>A), has also been reported in association with LQTS (Splawski I et al. Circulation. 2000;102(10):1178-85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: May 1, 2024