NM_000138.5(FBN1):c.989-1G>C AND Marfan syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 16, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000664040.2

Allele description [Variation Report for NM_000138.5(FBN1):c.989-1G>C]

NM_000138.5(FBN1):c.989-1G>C

Genes:

LOC113939944:Sharpr-MPRA regulatory region 9539 [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.989-1G>C

HGVS:

NC_000015.10:g.48520818C>G
NG_008805.2:g.129971G>C
NG_063729.1:g.387C>G
NM_000138.5:c.989-1G>CMANE SELECT
NM_001406716.1:c.989-1G>C
LRG_778t1:c.989-1G>C
LRG_778:g.129971G>C
NC_000015.9:g.48813015C>G
NM_000138.4:c.989-1G>C

Links:

dbSNP: rs1555400616

NCBI 1000 Genomes Browser:

rs1555400616

Molecular consequence:

NM_000138.5:c.989-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406716.1:c.989-1G>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

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LOC119648159 [Hermetia illucens]
LOC119648159 [Hermetia illucens]
Gene ID:119648159

Gene
MELTF [Pan paniscus]
MELTF [Pan paniscus]
Gene ID:100973912

Gene
HAS2 [Colobus angolensis palliatus]
HAS2 [Colobus angolensis palliatus]
Gene ID:105511038

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000787435	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Pathogenic (Nov 7, 2017)	germline	clinical testing
SCV004123030	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (Assertion Criteria VCEP FBN1 Version 1)	Pathogenic (Nov 16, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000787435

Center for Medical Genetics Ghent, University of Ghent

no assertion criteria provided

Pathogenic
(Nov 7, 2017)

germline

clinical testing

SCV004123030

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(Assertion Criteria VCEP FBN1 Version 1)

Pathogenic
(Nov 16, 2023)

germline

curation

Citation Link

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Summary from all submissions

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

Details of each submission

From Center for Medical Genetics Ghent, University of Ghent, SCV000787435.1

#	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 ClinGen FBN1 Variant Curation Expert Panel, ClinGen, SCV004123030.1

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

Description

NM_00138 c.989-1G>C in FBN1 is a splice site variant predicted to affect an acceptor splice site in intron 8 of the gene. Experimental cDNA sequencing studies have demonstrated that this variant disrupts mRNA splicing, causing the in-frame deletion of exon 9 and resulting in abnormal protein product (PVS1_strong; PMID: 15241795). This variant was found in one proband (reported twice in the literature) meeting the revised Ghent criteria for clinical diagnoses of Marfan syndrome (PP4; PMIDs: 15241795, 24161884); in one family, the variant was found to segregate with features of Marfan syndrome in at least 10 family members (PP1_strong; PMID: 15241795This variant has been reported 1 time in ClinVar as pathogenic (Variation ID: 549476). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1_strong, PP1_strong, PM2_supporting, PP4.

#	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: Nov 25, 2023

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