NM_005251.3(FOXC2):c.361C>T (p.Arg121Cys) AND none provided

Clinical significance:Likely pathogenic (Last evaluated: Feb 18, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001289872.1

Allele description [Variation Report for NM_005251.3(FOXC2):c.361C>T (p.Arg121Cys)]

NM_005251.3(FOXC2):c.361C>T (p.Arg121Cys)

Genes:
FOXC2-AS1:FOXC2 antisense RNA 1 [Gene - HGNC]
FOXC2:forkhead box C2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16q24.1
Genomic location:
Preferred name:
NM_005251.3(FOXC2):c.361C>T (p.Arg121Cys)
HGVS:
  • NC_000016.10:g.86567696C>T
  • NG_012025.1:g.5446C>T
  • NG_012025.2:g.5868C>T
  • NM_005251.3:c.361C>TMANE SELECT
  • NP_005242.1:p.Arg121Cys
  • LRG_1292t1:c.361C>T
  • LRG_1292:g.5868C>T
  • LRG_1292p1:p.Arg121Cys
  • NC_000016.9:g.86601302C>T
  • NM_005251.2:c.361C>T
  • NR_125795.1:n.66G>A
Protein change:
R121C; ARG121CYS
Links:
OMIM: 602402.0014; dbSNP: rs1567571184
NCBI 1000 Genomes Browser:
rs1567571184
Molecular consequence:
  • NM_005251.3:c.361C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_125795.1:n.66G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
none provided
Identifiers:
MedGen: CN235283

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001477871ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Feb 18, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001477871.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The FOXC2 c.361C>T; p.Arg121Cys variant is reported in the literature in several individuals affected with primary lymphedema (Lyons 2017, Sargent 2014, van Steensel 2009). This variant was found to segregate with disease in several members of a family with hereditary lymphedema (Sargent 2014). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 121 is highly conserved, and it occurs in the forkhead DNA-binding domain and interacts with bases in the DNA major groove (Li 2019). Functional assays show that the p.Arg121Cys variant lacks measurable transcriptional activation activity in cultured cells (van Steensel 2009). Additionally, another amino acid substitution at this codon (p.Arg121His) has been reported in an individual with hereditary lymphedema and lacks DNA-binding and transcriptional activation activity (Berry 2005). Based on available information, the p.Arg121Cys variant is considered to be likely pathogenic. References: Berry FB et al. The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis. Hum Mol Genet. 2005 Sep 15;14(18):2619-27. Li S et al. Crystal Structure of FOXC2 in Complex with DNA Target. ACS Omega. 2019 Jun 24;4(6):10906-10914. Lyons O et al. Human venous valve disease caused by mutations in FOXC2 and GJC2. J Exp Med. 2017 Jul 19. pii: jem.20160875. Sargent C et al. A five generation family with a novel mutation in FOXC2 and lymphedema worsening to hydrops in the youngest generation. Am J Med Genet A. 2014 Nov;164A(11):2802-7. van Steensel MA et al. Novel missense mutations in the FOXC2 gene alter transcriptional activity. Hum Mutat. 2009 Dec;30(12):E1002-9.

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

Last Updated: Jan 30, 2021

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