Submissions for variant NM_000138.5(FBN1):c.5504G>A (p.Cys1835Tyr)

dbSNP: rs111929350

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035227	SCV000058872	likely pathogenic	Marfan syndrome	2012-05-22	criteria provided, single submitter	clinical testing	The Cys1835Tyr variant has been reported in 2 individuals with clinical features of Marfan syndrome (Halliday 1999, Loeys 2001). Functional studies using patien t-derived fibroblasts have shown that the Cys1835Tyr variant impacts the extrace llular secretion of fibrillin-1 (Halliday 1999). However, this cellular system m ay not accurately represent biological function. This residue is highly conserve d across species and computational analyses (biochemical amino acid properties, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though th is information is not predictive enough to determine pathogenicity. The Cys1835T yr variant has been identified in 0.01% (1/1128) of chromosomes from a broad, th ough clinically and racially unspecified population (dbSNP rs111929350). This fr equency is not high enough to rule out a pathogenic role. Lastly, this variant a ffects a cysteine residue. Cysteine substitutions are a common finding in indivi duals with Marfan syndrome (Schrijver 1999). In summary, this variant is likely to be pathogenic, though further segregation studies and functional analyses are required to fully establish the pathogenicity of this variant.
GeneDx	RCV000181545	SCV000233848	pathogenic	not provided	2024-06-27	criteria provided, single submitter	clinical testing	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; Affects a cysteine residue within an 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 EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 17657824, 10647894, 11700157, 11933199, 12938084, 34550612, 38190127, 33174221, 11826022)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001384079	SCV001583458	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2020-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 1835 of the FBN1 protein (p.Cys1835Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Marfan syndrome (PMID: 10647894, 11700157, 11826022). ClinVar contains an entry for this variant (Variation ID: 42385). 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. 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.
3billion	RCV000035227	SCV002521673	likely pathogenic	Marfan syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042385). A different missense change at the same codon (p.Cys1835Ser) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000237099, VCV000549282). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.