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NM_000138.5(FBN1):c.5788+5G>A AND Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 16, 2023
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:
RCV000781375.7

Allele description [Variation Report for NM_000138.5(FBN1):c.5788+5G>A]

NM_000138.5(FBN1):c.5788+5G>A

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.5788+5G>A
HGVS:
  • NC_000015.10:g.48446701C>T
  • NG_008805.2:g.204088G>A
  • NM_000138.5:c.5788+5G>AMANE SELECT
  • LRG_778t1:c.5788+5G>A
  • LRG_778:g.204088G>A
  • NC_000015.9:g.48738898C>T
  • NM_000138.4:c.5788+5G>A
  • c.5788+5G>A
Nucleotide change:
IVS46+5G-A
Links:
OMIM: 134797.0039; dbSNP: rs193922219
NCBI 1000 Genomes Browser:
rs193922219
Molecular consequence:
  • NM_000138.5:c.5788+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections
Identifiers:
MedGen: CN229799

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000919354Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jan 16, 2023) 		germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies.

Hayward C, Brock DJ.

Hum Mutat. 1997;10(6):415-23. Review.

PubMed [citation]
PMID:
9401003

Mutant fibrillin-1 monomers lacking EGF-like domains disrupt microfibril assembly and cause severe marfan syndrome.

Liu W, Qian C, Comeau K, Brenn T, Furthmayr H, Francke U.

Hum Mol Genet. 1996 Oct;5(10):1581-7.

PubMed [citation]
PMID:
8894692
See all PubMed Citations (13)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919354.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (13)

Description

Variant summary: FBN1 c.5788+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. One predicts the variant weakens the canonical 5' splicing donor site. Two publications report experimental evidence suggesting that this variant causes skipping of exon 46 (Liu_1996; Nijbroek_1995). The variant was absent in 251390 control chromosomes. c.5788+5G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (example, Baetens_2011, Liu_1996, Nijbroek_1995, Rand-Hendriksen_2007, Stheneur_2009). These data indicate that the variant is very likely to be associated with disease. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Apr 20, 2024