NM_000138.5(FBN1):c.2113+1G>A AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 12, 2021
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:: RCV000707068.5

Allele description [Variation Report for NM_000138.5(FBN1):c.2113+1G>A]

NM_000138.5(FBN1):c.2113+1G>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.2113+1G>A

HGVS:

NC_000015.10:g.48503786C>T
NG_008805.2:g.147003G>A
NM_000138.5:c.2113+1G>AMANE SELECT
NM_001406716.1:c.2113+1G>A
LRG_778t1:c.2113+1G>A
LRG_778:g.147003G>A
NC_000015.9:g.48795983C>T
NM_000138.4:c.2113+1G>A

Links:

dbSNP: rs1566913670

NCBI 1000 Genomes Browser:

rs1566913670

Molecular consequence:

NM_000138.5:c.2113+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406716.1:c.2113+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Marfan syndrome (MFS)
Synonyms:: MARFAN SYNDROME, TYPE I; Marfan syndrome type 1; Marfan's syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007947; MedGen: C0024796; Orphanet: 284963; Orphanet: 558; OMIM: 154700

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000836148	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 12, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26787436, 16199547, 17657824, 19293843, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000836148

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 12, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype impacts survival in Marfan syndrome.

Franken R, Groenink M, de Waard V, Feenstra HM, Scholte AJ, van den Berg MP, Pals G, Zwinderman AH, Timmermans J, Mulder BJ.

Eur Heart J. 2016 Nov 14;37(43):3285-3290. Epub 2016 Jan 18.

PubMed [citation]

PMID:: 26787436

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000836148.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 26787436; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 17 of the FBN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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