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

CA392347946

549476 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 80898e5d-210e-4079-a00b-1c94b048453c

Approved on: 2023-11-16

Published on: 2023-11-16

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: PP1_Strong PVS1_Strong PM2_Supporting PP4

• Not Met criteria codes: BS2 BS3 BS1 BP7 BP3 BP4 BP1 BP2 PS1 PS3 PS2 PS4 PP3 PP2 BA1 PM6 PM1 PM5 PM4 PM3

Expert Panel

FBN1 VCEP

Criteria Specification Information

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

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
• PVS1_Strong: functional studies demonstrating it results in exon 9 deletion (in-frame)
• PM2_Supporting: absent from gnomAD
• PP4: proband with SS=8 and TAAD (meets revised Ghent criteria)

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
• BP7: 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
• 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
• 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
• BA1: 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
• 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