NM_001999.4(FBN2):c.539G>A (p.Cys180Tyr) AND Cardiovascular phenotype

Clinical significance:Likely pathogenic (Last evaluated: Sep 1, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000618247.1

Allele description [Variation Report for NM_001999.4(FBN2):c.539G>A (p.Cys180Tyr)]

NM_001999.4(FBN2):c.539G>A (p.Cys180Tyr)

Gene:
FBN2:fibrillin 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q23.3
Genomic location:
Preferred name:
NM_001999.4(FBN2):c.539G>A (p.Cys180Tyr)
HGVS:
  • NC_000005.10:g.128519362C>T
  • NG_008750.1:g.23681G>A
  • NM_001999.4:c.539G>AMANE SELECT
  • NP_001990.2:p.Cys180Tyr
  • NC_000005.9:g.127855055C>T
  • NM_001999.3:c.539G>A
Protein change:
C180Y
Links:
dbSNP: rs1554075372
NCBI 1000 Genomes Browser:
rs1554075372
Molecular consequence:
  • NM_001999.4:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000738981Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Sep 1, 2016)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Structure of the fibrillin-1 N-terminal domains suggests that heparan sulfate regulates the early stages of microfibril assembly.

Yadin DA, Robertson IB, McNaught-Davis J, Evans P, Stoddart D, Handford PA, Jensen SA, Redfield C.

Structure. 2013 Oct 8;21(10):1743-56. doi: 10.1016/j.str.2013.08.004. Epub 2013 Sep 12.

PubMed [citation]
PMID:
24035709
PMCID:
PMC3794157

Details of each submission

From Ambry Genetics, SCV000738981.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The p.C180Y variant (also known as c.539G>A), located in coding exon 5 of the FBN2 gene, results from a G to A substitution at nucleotide position 539. The cysteine at codon 180 is replaced by tyrosine, an amino acid with highly dissimilar properties. Internal structure analysis reveals that this alteration would result in loss of an EGF-defining disulfide motif and is likely to cause large structural destabilization of the N-terminal domain (Yadin DA et al. Structure, 2013 ;21:1743-56). In one study, 13 of 14 reported FBN2 mutations were found in the middle region of the gene (exons 24-36), and 7 of these mutations were noted to alter or produce a cysteine residue (Callewaert BL et al. Hum Mutat. 2009;30(3):334-341). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. 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
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Dec 7, 2020

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