rs794728326
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.1426T>G(p.Cys476Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C476R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.1426T>G | p.Cys476Gly | missense_variant | 12/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.1426T>G | p.Cys476Gly | missense_variant | 11/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.1426T>G | p.Cys476Gly | missense_variant | 12/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 15, 2016 | - - |
Marfan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 17, 2019 | The p.Cys476Gly variant in FBN1 has been identified in at least 4 individuals with Marfan syndrome, segregated in 33 affected relatives from one family, and was absent in 19 unaffected family members from that same family (Piersall 1994, Somers 2016, Vatti 2017). In addition, this variant was absent from large population studies. Two other variants at the same position (p.Cys476Arg and p.Cys476Ser) have also been identified in individuals with Marfan syndrome, suggesting that changes at this position are not tolerated. Studies provide some evidence that this variant impacts protein function (Schrijver 1999). Furthermore, this variant affects a highly conserved cysteine residue in the EGF-like domains, which is a common finding in individuals with Marfan syndrome (Schrijver 1999). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PP1_Strong; PM1; PM2; PS4_Moderate; PP3, PS3_Supporting. - |
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 12, 2016 | Variant summary: The FBN1 c.1426T>G (p.Cys476Gly) variant located in an EGF-like domain (via InterPro) alters a cysteine, which plays a key role in disulfide binding, important for proper fibrillin function. 4/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a damaging outcome, which is supported by a functional study, Schrijver_1999. The variant of interest was not observed in controls (ExAC, 1000 Gs, ESP, or publication controls) and has been reported in multiple affected individuals including a large family that segregates with disease, Piersall_1994. Multiple reputable clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2022 | Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7951214, 10486319, 27112580, 28941062) - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 476 of the FBN1 protein (p.Cys476Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 7951214, 10486319, 27112580). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200179). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at