chr15-48446747-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1_StrongPP2PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_00138 c.5747G>A, is a missense variant in FBN1predicted to cause a substitution of a cysteine by tyrosine at amino acid 1916 (p.Cys1916Tyr). This variant was found in a proband diagnosed with Marfan syndrome (PMID 24793577, PP4). This variant has been reported three times in ClinVar: once as pathogenic, once as likely pathogenic, and once as uncertain significance (Variation ID: 42391). This variant is not present in gnomAD(PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). 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). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.967, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). 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, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA016026/MONDO:0007947/022
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:2
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The NM_00138 c.5747G>A, is a missense variant in FBN1predicted to cause a substitution of a cysteine by tyrosine at amino acid 1916 (p.Cys1916Tyr). This variant was found in a proband diagnosed with Marfan syndrome (PMID 24793577, PP4). This variant has been reported three times in ClinVar: once as pathogenic, once as likely pathogenic, and once as uncertain significance (Variation ID: 42391). This variant is not present in gnomAD(PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). 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). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.967, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). 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, PP4. -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys1916 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19293843; Invitae), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 42391). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 24793577). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1916 of the FBN1 protein (p.Cys1916Tyr). -
not specified Uncertain:1
Variant summary: FBN1 c.5747G>A (p.Cys1916Tyr) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245812 control chromosomes. c.5747G>A has been reported in the literature in individuals affected with MFS (Lerner-Ellis_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified a VUS - possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at