Evidence Repository - Clinical Genome Resources

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Variant: NM_000138.5(FBN1):c.1708T>C (p.Cys570Arg)

CA269554328

956400 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 38d36d10-5c7c-455c-9338-0706c4a6f7f9

Approved on: 2023-11-16

Published on: 2023-11-16

HGVS expressions

NM_000138.5:c.1708T>C

NM_000138.5(FBN1):c.1708T>C (p.Cys570Arg)

NC_000015.10:g.48510050A>G

CM000677.2:g.48510050A>G

NC_000015.9:g.48802247A>G

CM000677.1:g.48802247A>G

NC_000015.8:g.46589539A>G

NG_008805.2:g.140739T>C

ENST00000684448.1:n.382T>C

ENST00000316623.10:c.1708T>C

ENST00000316623.9:c.1708T>C

ENST00000537463.6:c.636+27661T>C

NM_000138.4:c.1708T>C

Pathogenic

PM1_Strong PS4_Moderate PS3_Supporting PP3 PP2 PP4 PM2_Supporting

BS2 BS4 BS3 BS1 PVS1 PS2 PS1 BP5 BP2 BP3 BP4 PP1 BA1 PM6 PM3 PM4 PM5

Evidence Links 1

Expert Panel

FBN1 VCEP

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.1708T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 570 (p.Cys570Arg). This variant has been found in two probands with ectopia lentis (EL), one of whom was also reported to have numerous systemic features of Marfan syndrome without thoracic aortic aneurysm and dissection (TAAD), as well as a proband with isolated TAAD (PS4_moderate; PMID: 10486319; 3billion & Invitae internal data, ClinVar Variation ID: 956400). An additional proband with a severe Marfan syndrome phenotype including EL, TAAD, and major skeletal involvement (PP4; Bichat internal data). Functional studies performed on patient fibroblasts with this variant demonstrated reduced fibrillin synthesis and secretion (50% and 28% of controls, respectively) (PS3_supporting; PMID: 10486319). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium binding EGF domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Several other variants affecting this codon have been reported in association with Marfan syndrome (p.Cys570Gly, p.Cys570SerSer, p.Cys570Trp, p.Cys570Tyr). Computational prediction tools and conservation analysis support that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). 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: PM1_strong, PS4_moderate, PS3_supporting, PM2_supporting, PP2, PP3, PP4.

PM1_Strong

Cysteine in cbEGF4

PS4_Moderate

3 probands worth 2.5 PS4 points

PS3_Supporting

acceptable functional assay per FBN1 VCEP; per ClinGen SVI the study was lacking sufficient replicates to use at full strength

Study of fibroblasts from patient with p.Cys570Arg (patient cited in PS4 evidence); studies demonstrated reduced fibrillin synthesis (50% of wild type/control) and reduced fibrillin secretion (28% of wild type/control) PubMed:10486319

PP3

REVEL = 0.983

PP2