rs1555394580
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP2PP3PM1PM5PS4_SupportingPM2_Supporting
This summary comes from the ClinGen Evidence Repository: NM_00138 c. 7016G>A is a missense variant in FBN1 predicted to cause a substitution of cysteine by tyrosine at amino acid 2339 (p.Cys2339Tyr). This variant has been identified in one individual with clinical features of Marfan syndrome (PS4_Sup). This variant has been reported 1 time in ClinVar as Likely pathogenic and 1 time as uncertain significance (VariationID:495644).This variant is not present in gnomAD (PM2_Sup; https://gnomad.broadinstitute.org/ v4.0.0). This variant affects a cysteine residue in a TB domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1). 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, PM5, PS4_Sup, PM2_Sup, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA392330332/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 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.7016G>A | p.Cys2339Tyr | missense_variant | 58/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.7016G>A | p.Cys2339Tyr | missense_variant | 57/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.7016G>A | p.Cys2339Tyr | missense_variant | 58/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 08, 2018 | The p.Cys2339Tyr variant in FBN1 has been reported in 1 individual with clinical features of Marfan syndrome (Katzke 2002) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that t he p.Cys2339Tyr variant may impact the protein. Two other variants at this amino acid position (p.Cys2239Gly, p.Cys2239arg) have also been reported in individua ls with Marfan syndrome (Rybczynski 2008, Ogawa 2011), suggesting that changes a t this position may not be tolerated. In addition, the p.Cys2339Tyr variant affe cts a cysteine residue; cysteine substitutions are a common finding in individua ls with Marfan syndrome (Schrijver 1999). In summary, although additional studie s are required to fully establish its clinical significance, the p.Cys2339Tyr va riant is likely pathogenic. ACMG/AMP Criteria applied (Richards 2015): PM1; PM2; PP3; PS4_supporting. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 17, 2017 | Variant summary: The FBN1 c.7016G>A (p.Cys2339Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index) although these predictions have yet to be functionally assessed. This variant is absent in 119,502 control chromosomes. The variant of interest lies in a conserved region within a TGF-beta binding (TB) domain. Many manifestations of Marfan syndrome relate to excess activation and signaling by the growth factor TGF-beta (Dietz_2005)." This variant determines the substitution of cysteine with tyrosine. 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. Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. Additionally, this variant was reported in a patient with Marfan syndrome. No clinical laboratories cite the variant of interest. Therefore, taking all available lines of evidence, the variant of interest is classified as VUS-possibly pathogenic until additional information becomes available. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at