The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000138.5(FBN1):c.6820T>C (p.Cys2274Arg)

CA353663

222610 (ClinVar)

Gene: FBN1
Condition: Marfan syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 67a42422-1e18-4754-b1ba-f80eabdff6a2
Approved on: 2024-08-22
Published on: 2024-08-22

HGVS expressions

NM_000138.5:c.6820T>C
NM_000138.5(FBN1):c.6820T>C (p.Cys2274Arg)
NC_000015.10:g.48430722A>G
CM000677.2:g.48430722A>G
NC_000015.9:g.48722919A>G
CM000677.1:g.48722919A>G
NC_000015.8:g.46510211A>G
NG_008805.2:g.220067T>C
ENST00000559133.6:c.6820T>C
ENST00000674301.2:c.*271T>C
ENST00000682170.1:n.429T>C
ENST00000316623.10:c.6820T>C
ENST00000674301.1:c.1924T>C
ENST00000316623.9:c.6820T>C
ENST00000559133.5:c.2127T>C
ENST00000560720.1:n.107T>C
NM_000138.4:c.6820T>C
More

Likely Pathogenic

Met criteria codes 4
PM1_Strong PM2_Supporting PP3 PP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
FBN1 VCEP
NM_00138 c.6820T>C is a missense variant in FBN1 predicted to cause a substitution of cysteine by arginine at amino acid 2274 (p.Cys2274Arg). This variant is not reported in the literature. This variant has been reported twice in ClinVar as Likely pathogenic and once as uncertain significance (Variation ID: 222610). This variant is not present in gnomAD (PM2_Sup; https://gnomad.broadinstitute.org/ v4.0.0). 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). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.992, PP3). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PM2_Sup,PP2, PP3
Met criteria codes
PM1_Strong
Cys- disrupting residue in cbEGF-like domain
PM2_Supporting
Absent in gnomAD.
PP3
REVEL score: 0.992
PP2
The constraint z-score for missense variants affecting FBN1 is 5.06.
Curation History
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