Submissions for variant NM_000138.5(FBN1):c.3413G>C (p.Cys1138Ser)

dbSNP: rs397515791

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588454	SCV000695510	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2017-07-26	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.3413G>C (p.Cys1138Ser) variant involves the alteration of a conserved nucleotide which lies within a conserved region in EGF-like #13. "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. In support of a deleterious effect of this variant, 4/4 in silico analyses predict a damaging outcome, absent from 121410 control chromosomes (ExAC), reported de novo occurrence in a classic MFS patient via publication, and additional variants affecting the same amino acid, c.3413G>T (p.Cys1138Phe) and c.3412T>C (p.Cys1138Arg) reported by ClinVar as likely pathogenic indicating a mutational hotspot. Taken together, this variant is has been classified as a "likely pathogenic."
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027821	SCV001190441	likely pathogenic	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-03-30	criteria provided, single submitter	clinical testing	FBN1 NM_000138.4 exon 27 p.Cys1138Ser (c.3413G>C): This variant has been reported in the literature as de novo in one individual with classic Marfan syndrome (Stheneur 2009 PMID:19293843). This variant is not present in large control databases but is present in ClinVar (Variation ID:495590). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, this variant is predicted to affect a cysteine residue. Cysteine in the FBN1 gene is reported to have important functional relevance; variants that involve a cysteine residue are reported to be particularly significant (Dietz 1992 PMID:1301946). In addition, several other variants (p.Cys1138Arg, p.Cys1138Gly, p.Cys1138Phe) at this position have been reported in individuals with Marfan syndrome, supporting the potential functional relevance of this codon. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Centre of Medical Genetics, University of Antwerp	RCV002246001	SCV002025581	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS2, PP4
Invitae	RCV002530892	SCV003442924	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-07-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 495590). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 19293843). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1138 of the FBN1 protein (p.Cys1138Ser).