Variant: NM_000138.5(FBN1):c.7763A>G (p.Tyr2588Cys)

CA392324665

571222 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: fa2a7c59-1b12-4c8b-a029-5376bee76ea7

Approved on: 2024-08-22

Published on: 2024-08-22

HGVS expressions

NM_000138.5:c.7763A>G
NM_000138.5(FBN1):c.7763A>G (p.Tyr2588Cys)
NC_000015.10:g.48420743T>C
CM000677.2:g.48420743T>C
NC_000015.9:g.48712940T>C
CM000677.1:g.48712940T>C
NC_000015.8:g.46500232T>C
NG_008805.2:g.230046A>G
ENST00000559133.6:c.*571A>G
ENST00000674301.2:c.*1276A>G
ENST00000682170.1:n.1944A>G
ENST00000682767.1:n.1060A>G
ENST00000316623.10:c.7763A>G
ENST00000674301.1:c.2929A>G
ENST00000316623.9:c.7763A>G
ENST00000559133.5:c.3132A>G
NM_000138.4:c.7763A>G

Uncertain Significance

• Met criteria codes: PP3 PP2 PM1 PM2_Supporting

• Not Met criteria codes: PS2 PP4

Expert Panel

FBN1 VCEP

Criteria Specification Information

Evidence submitted by expert panel

FBN1 VCEP

The NM_00138 c.7763A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 2588 (p.Tyr2588Cys). This cysteine-creating variant impacts a tyrosine within a calcium-binding (cb) (D)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain, important for protein stability (PM1, PMID 10766875, 26281765). This variant has been reported twice in ClinVar: once as likely pathogenic, and once as uncertain significance (Variation ID: 571222). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.915, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to insufficient evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM2_Sup, PP2, PP3.

Met criteria codes

• PP3: REVEL score: 0.915
• PP2: Missense
• PM1: Cys-creating variant in a cbEGF-like domain; impacting a Tyr in the calcium-binding (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence
• PM2_Supporting: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Not Met criteria codes

• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline