NM_000138.5(FBN1):c.7454-1G>C AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 7, 2020
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:: RCV001386073.7

Allele description [Variation Report for NM_000138.5(FBN1):c.7454-1G>C]

NM_000138.5(FBN1):c.7454-1G>C

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.7454-1G>C

HGVS:

NC_000015.10:g.48422069C>G
NG_008805.2:g.228720G>C
NM_000138.5:c.7454-1G>CMANE SELECT
NM_001406716.1:c.7454-1G>C
LRG_778:g.228720G>C
NC_000015.9:g.48714266C>G

Links:

dbSNP: rs2141222615

NCBI 1000 Genomes Browser:

rs2141222615

Molecular consequence:

NM_000138.5:c.7454-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406716.1:c.7454-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

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

Recent activity

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Karyopherin alpha 3 (importin alpha 4) [Homo sapiens]
Karyopherin alpha 3 (importin alpha 4) [Homo sapiens]
gi|16878323|gb|AAH17355.1|

Protein
Mus musculus oxysterol binding protein, mRNA (cDNA clone IMAGE:2651122), partial...
Mus musculus oxysterol binding protein, mRNA (cDNA clone IMAGE:2651122), partial cds
gi|13097404|gb|BC003443.1|

Nucleotide
Gm33910 predicted gene, 33910 [Mus musculus]
Gm33910 predicted gene, 33910 [Mus musculus]
Gene ID:102636992

Gene
102636992[uid] AND (alive[prop]) (1)
Gene
uncharacterized protein LOC101213787 isoform X1 [Cucumis sativus]
uncharacterized protein LOC101213787 isoform X1 [Cucumis sativus]
gi|449463198|ref|XP_004149321.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001586164	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 7, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16199547, 17657824, 19293843, 16222657, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001586164

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 7, 2020)

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

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

The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations.

Comeglio P, Johnson P, Arno G, Brice G, Evans A, Aragon-Martin J, da Silva FP, Kiotsekoglou A, Child A.

Hum Mutat. 2007 Sep;28(9):928.

PubMed [citation]

PMID:: 17657824

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001586164.4

#	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. Donor and acceptor splice site variants 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). Disruption of this splice site has been observed in individual(s) with Marfan syndrome (PMID: 16222657, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 60 of the FBN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

#	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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