NM_000138.5(FBN1):c.6032G>A (p.Cys2011Tyr) AND Cardiovascular phenotype

Clinical significance:Likely pathogenic (Last evaluated: Mar 19, 2015)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000242615.1

Allele description [Variation Report for NM_000138.5(FBN1):c.6032G>A (p.Cys2011Tyr)]

NM_000138.5(FBN1):c.6032G>A (p.Cys2011Tyr)

Gene:
FBN1:fibrillin 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q21.1
Genomic location:
Preferred name:
NM_000138.5(FBN1):c.6032G>A (p.Cys2011Tyr)
HGVS:
  • NC_000015.10:g.48444546C>T
  • NG_008805.2:g.206243G>A
  • NM_000138.5:c.6032G>AMANE SELECT
  • NP_000129.3:p.Cys2011Tyr
  • NP_000129.3:p.Cys2011Tyr
  • LRG_778t1:c.6032G>A
  • LRG_778:g.206243G>A
  • LRG_778p1:p.Cys2011Tyr
  • NC_000015.9:g.48736743C>T
  • NM_000138.4:c.6032G>A
Protein change:
C2011Y
Links:
dbSNP: rs886038967
NCBI 1000 Genomes Browser:
rs886038967
Molecular consequence:
  • NM_000138.5:c.6032G>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
SCV000319401Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Mar 19, 2015)
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

Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities.

Robinson DO, Lin F, Lyon M, Raponi M, Cross E, White HE, Cox H, Clayton-Smith J, Baralle D.

Clin Genet. 2012 Sep;82(3):223-31. doi: 10.1111/j.1399-0004.2011.01781.x. Epub 2011 Sep 30.

PubMed [citation]
PMID:
21895641

Details of each submission

From Ambry Genetics, SCV000319401.5

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

Description

The p.C2011Y variant (also known as c.6032G>A), located in coding exon 48 of the FBN1 gene, results from a G to A substitution at nucleotide position 6032. The cysteine at codon 2011 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #30 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Internal structural analysis indicates that this alteration eliminates a structurally critical disulfide in the structurally sensitive cbEGF domain #30 (Ambry internal data). A likely pathogenic alteration, p.C2011R, has been described in the same codon (Overwater E et al. Hum. Mutat., 2018 Sep;39:1173-1192). 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 4, 2021

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