Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document

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

CA392347946

549476 (ClinVar)

Gene: FBN1
Condition: Marfan syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 80898e5d-210e-4079-a00b-1c94b048453c

HGVS expressions

NM_000138.5:c.989-1G>C
NM_000138.5(FBN1):c.989-1G>C
NC_000015.10:g.48520818C>G
CM000677.2:g.48520818C>G
NC_000015.9:g.48813015C>G
CM000677.1:g.48813015C>G
NC_000015.8:g.46600307C>G
NG_008805.2:g.129971G>C
ENST00000316623.10:c.989-1G>C
ENST00000316623.9:c.989-1G>C
ENST00000537463.6:c.636+16893G>C
NM_000138.4:c.989-1G>C

Pathogenic

Met criteria codes 4
PP1_Strong PM2_Supporting PP4 PVS1_Strong
Not Met criteria codes 20
BS2 BS3 BS1 BP3 BP4 BP1 BP2 BP7 PS1 PS3 PS2 PS4 BA1 PP3 PP2 PM1 PM5 PM4 PM3 PM6

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen FBN1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
FBN1 VCEP
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.
Met criteria codes
PP1_Strong
10 segregations with features of MFS in one family
PM2_Supporting
absent from gnomAD
PP4
proband with SS=8 and TAAD (meets revised Ghent criteria)
PVS1_Strong
functional studies demonstrating it results in exon 9 deletion (in-frame)
Not Met criteria codes
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
Functional data (cDNA sequencing) showing deletion of exon 9 (in-frame); data accounted for in application of PVS1_strong
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
1 published proband, accounted for in PP4 criterion
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-11-16
Published on: 2023-11-16
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.