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NM_000138.5(FBN1):c.1837+5G>A AND Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 23, 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:
RCV003117440.2

Allele description [Variation Report for NM_000138.5(FBN1):c.1837+5G>A]

NM_000138.5(FBN1):c.1837+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.1837+5G>A
HGVS:
  • NC_000015.10:g.48508577C>T
  • NG_008805.2:g.142212G>A
  • NM_000138.5:c.1837+5G>AMANE SELECT
  • LRG_778t1:c.1837+5G>A
  • LRG_778:g.142212G>A
  • NC_000015.9:g.48800774C>T
  • NM_000138.4:c.1837+5G>A
Links:
dbSNP: rs1445085747
NCBI 1000 Genomes Browser:
rs1445085747
Molecular consequence:
  • NM_000138.5:c.1837+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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003800652Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jan 23, 2023) 		germlineclinical testing

PubMed (5)
[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

Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy.

Biggin A, Holman K, Brett M, Bennetts B, Adès L.

Hum Mutat. 2004 Jan;23(1):99.

PubMed [citation]
PMID:
14695540

Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome.

Hung CC, Lin SY, Lee CN, Cheng HY, Lin SP, Chen MR, Chen CP, Chang CH, Lin CY, Yu CC, Chiu HH, Cheng WF, Ho HN, Niu DM, Su YN.

Ann Hum Genet. 2009 Nov;73(Pt 6):559-67. doi: 10.1111/j.1469-1809.2009.00545.x.

PubMed [citation]
PMID:
19839986
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003800652.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: FBN1 c.1837+5G>A alters a 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: One predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251316 control chromosomes. c.1837+5G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (Franken_2016, Franken_2017) and other related phenotypes: Dural Ectasia (Hung_2009) and Ectopia Lentis (Biggin_2004, Overwater_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=1), Likely Pathogenic (n=4) and Pathogenic (n=1). 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: May 7, 2024