NM_000138.4(FBN1):c.461G>C (p.Cys154Ser) AND not provided

Clinical significance:Likely pathogenic (Last evaluated: Aug 16, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000433676.1

Allele description

NM_000138.4(FBN1):c.461G>C (p.Cys154Ser)

Gene:
FBN1:fibrillin 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q21.1
Genomic location:
Preferred name:
NM_000138.4(FBN1):c.461G>C (p.Cys154Ser)
HGVS:
  • NC_000015.10:g.48596360C>G
  • NG_008805.2:g.54429G>C
  • NM_000138.4:c.461G>C
  • NP_000129.3:p.Cys154Ser
  • LRG_778t1:c.461G>C
  • LRG_778:g.54429G>C
  • LRG_778p1:p.Cys154Ser
  • NC_000015.9:g.48888557C>G
Protein change:
C154S
Links:
dbSNP: rs1057521103
NCBI 1000 Genomes Browser:
rs1057521103
Molecular consequence:
  • NM_000138.4:c.461G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000521076GeneDxcriteria provided, single submitter
Likely pathogenic
(Aug 16, 2016)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000521076.3

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

Description

A variant of uncertain significance has been identified in the FBN1 gene. The C154S variant has previously been reported in a 14 year-old patient with ectopia lentis, dilatation of the ascending aorta, mitral valve prolapse, striae atrophica, multiple skeletal findings including pectus carinatum, joint hypermobility, and a high arched palate with dental crowding, and a characteristic facial appearance (Biggin et al., 2004); however, segregation analysis was not performed. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C154S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, although the C154S variant affects a Cysteine residue, it does not occur within a calcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.

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

Last Updated: Jul 9, 2018

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