Submissions for variant NM_000138.5(FBN1):c.7003C>G (p.Arg2335Gly)

dbSNP: rs794728262

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588390	SCV000695593	uncertain significance	not provided	2016-09-07	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.7003C>G (p.Arg2335Gly) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant. The variant lies in EGF-like calcium-binding domain; Cys substitution is known to be deleterious in such domains. Another missense change at the same residue, p.Arg2335Trp, has been reported in patients with Marfan syndrome in literature and is classified as pathogenic by a lab in ClinVar. This variant is absent in 116790 control chromosomes from ExAC. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003767332	SCV004608527	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-07-13	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg2335 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12203992, 29357934; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 495643). This missense change has been observed in individual(s) with FBN1-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2335 of the FBN1 protein (p.Arg2335Gly). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.