NM_000138.5(FBN1):c.4460-8G>A AND Marfan syndrome

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jul 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000029737.9

Allele description [Variation Report for NM_000138.5(FBN1):c.4460-8G>A]

NM_000138.5(FBN1):c.4460-8G>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.4460-8G>A

HGVS:

NC_000015.10:g.48468542C>T
NG_008805.2:g.182247G>A
NM_000138.5:c.4460-8G>AMANE SELECT
LRG_778t1:c.4460-8G>A
LRG_778:g.182247G>A
NC_000015.9:g.48760739C>T
NM_000138.4:c.4460-8G>A

Links:

dbSNP: rs193922204

NCBI 1000 Genomes Browser:

rs193922204

Molecular consequence:

NM_000138.5:c.4460-8G>A - intron variant - [Sequence Ontology: SO:0001627]

Observations:

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000052390	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	likely pathogenic (Aug 18, 2011)	germline	curation, clinical testing	PubMed (2) [See all records that cite these PMIDs] 15241795, 11700157 Citation Link,
SCV000263915	Blueprint Genetics	criteria provided, single submitter (Variant Classification)	Pathogenic (Nov 13, 2015)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11700157, 18087243, 19293843 Citation Link,
SCV000787066	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Likely pathogenic (Nov 7, 2017)	germline	clinical testing
SCV002766718	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 11700157, 18087243, 19293843, 20301510, 27274304, 29357934, 31950671, 32679894, 25741868
SCV004847813	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Aug 7, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11700157, 19293843, 15241795, 18087243, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	2	not provided	clinical testing, curation
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

FBN1-Related Marfan Syndrome.

Dietz H.

2001 Apr 18 [updated 2022 Feb 17]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301510

Marfan syndrome: current perspectives.

Pepe G, Giusti B, Sticchi E, Abbate R, Gensini GF, Nistri S.

Appl Clin Genet. 2016;9:55-65. doi: 10.2147/TACG.S96233. Review.

PubMed [citation]

PMID:: 27274304
PMCID:: PMC4869846

See all PubMed Citations (10)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052390.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	curation	PubMed (2)
2	not provided	1	not provided	not provided	curation	PubMed (2)
3	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

"Variant found in 14 yr old pt with classic MFS with major involvement of skeletal system, Ocular system and cardiovascular systtem, no involvement of pulmonary system , minor involvement of skin, no family history; unclear whether controls were tested for this variant.": PubMed [ID: 11700157]

Description

Converted during submission to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	unknown	not provided	Blood	assert pathogenicity		not provided	not provided	not provided	See 3

Co-occurrences

#	Zygosity	Alleles	Number of Observations
3	SingleHeterozygote	FBN1:c.6997+17C>G, FBN1:c.1415G>A	1

From Blueprint Genetics, SCV000263915.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

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

From Center for Medical Genetics Ghent, University of Ghent, SCV000787066.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766718.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have rarely been reported (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been confirmed by reverse transcriptase PCR (RT-PCR) to activate a cryptic acceptor splice site resulting in an insertion of six intronic nucleotides in exon 36 (c.4459_4460insTTTTAG). The variant results in an in-frame insertion of two amino acids in the protein sequence, p.(Thr1486_Asp1487insValLeu) (PMID: 18087243). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0705 - No comparable non canonical splice variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in >10 individuals with Marfan syndrome and ectopia lentis (ClinVar, PMID: 18087243, 11700157, 19293843, 32679894, doi:10.57204/001c.38690). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847813.1

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

Description

The c.4460-8G>A variant in FBN1 has been reported in at least 3 individuals with Marfan syndrome and segregated with disease in 2 affected individuals from 1 family (Loeys 2001, Pepe 2007, Stheneur 2009). It has also been identified in 0.003% (1/34574) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 36075). This variant is located in the 3' splice region. Computational tools and in vitro splicing assays (Pepe 2007) predict a splicing impact, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM2, PP3, PS3_Supporting, PS4_Moderate.

#	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: Aug 25, 2024

ClinVar

Relating variation to medicine