ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4121G>A (p.Cys1374Tyr)

dbSNP: rs2141279835
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002007163 SCV002236421 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2021-11-22 criteria provided, single submitter clinical testing 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 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 tyrosine, which is neutral and polar, at codon 1374 of the FBN1 protein (p.Cys1374Tyr). 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.
Fulgent Genetics, Fulgent Genetics RCV002492115 SCV002804001 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 2022-05-23 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV004598165 SCV005092630 pathogenic not provided 2024-07-01 criteria provided, single submitter clinical testing FBN1: PM1:Strong, PM2, PM5, PP3, PS4:Supporting

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