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NM_000218.3(KCNQ1):c.1771C>A (p.Arg591Ser) AND Long QT syndrome 1

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 15, 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:
RCV004555195.1

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1771C>A (p.Arg591Ser)]

NM_000218.3(KCNQ1):c.1771C>A (p.Arg591Ser)

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.1771C>A (p.Arg591Ser)
HGVS:
  • NC_000011.10:g.2778014C>A
  • NG_008935.1:g.338024C>A
  • NM_000218.3:c.1771C>AMANE SELECT
  • NM_001406836.1:c.1675C>A
  • NM_001406837.1:c.1501C>A
  • NM_001406838.1:c.1231C>A
  • NM_001406839.1:c.283C>A
  • NM_181798.2:c.1390C>A
  • NP_000209.2:p.Arg591Ser
  • NP_000209.2:p.Arg591Ser
  • NP_001393765.1:p.Arg559Ser
  • NP_001393766.1:p.Arg501Ser
  • NP_001393767.1:p.Arg411Ser
  • NP_001393768.1:p.Arg95Ser
  • NP_861463.1:p.Arg464Ser
  • NP_861463.1:p.Arg464Ser
  • LRG_287t1:c.1771C>A
  • LRG_287t2:c.1390C>A
  • LRG_287:g.338024C>A
  • LRG_287p1:p.Arg591Ser
  • LRG_287p2:p.Arg464Ser
  • NC_000011.9:g.2799244C>A
  • NM_000218.2:c.1771C>A
  • NM_181798.1:c.1390C>A
  • NR_040711.2:n.1664C>A
Protein change:
R411S
Molecular consequence:
  • NM_000218.3:c.1771C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406836.1:c.1675C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406837.1:c.1501C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406838.1:c.1231C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406839.1:c.283C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.2:c.1390C>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Long QT syndrome 1 (LQT1)
Identifiers:
MONDO: MONDO:0100316; MedGen: C4551647; Orphanet: 101016; Orphanet: 768; OMIM: 192500

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005044142New York Genome Center - PrenatalSEQ
criteria provided, single submitter

(NYGC Assertion Criteria 2020)		Likely pathogenic
(Sep 15, 2022) 		inheritedclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedinheritedunknown1not providednot provided1not providedclinical testing

Details of each submission

From New York Genome Center - PrenatalSEQ, SCV005044142.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.1771C>A variant in KCNQ1 has not previously been reported in the literature or public variant repositories (ClinVar and LOVD), and is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases.The c.1771C>A variant in KCNQ1 is located in exon 15 of this 16-exon gene, and is predicted to replace an evolutionarily conserved arginine amino acid with serine at position 591 in the coiled-coiled region of the encoded protein. In silico predictions are moderately in favor of damaging effect for the p.(Arg591Ser) variant [CADD v1.6 = 26, REVEL = 0.912]; however, there are no functional studies to support or refute these predictions. Variants affecting the same residue (p.(Arg591His), p.(Arg591Cys), p.(Arg591Leu)) and nearby residues (p.(Ala590Thr), p.(Gly589Asp), p.(Arg594Gln)) have been reported in the literature [PMID: 10024302, 17470695, 22949429, 23158531, 29622001, 31737537, 32383558, 34505893, 34860437] and ClinVar [ClinVar IDs: 3140, 53015, 53016, 53017, 53018, 200857] in individuals with long QT syndrome. Functional studies demonstrated reduced channel current activity for the p.Arg591His variant supporting the functional importance of the p.Arg591 residue [PMID: 16253915]. Based on available evidence this inherited heterozygous c.1771C>A p.(Arg591Ser) variant identified in KCNQ1 is classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedunknown1not providednot provided1not providednot providednot provided

Last Updated: May 26, 2024