Submissions for variant NM_000138.5(FBN1):c.700G>T (p.Gly234Cys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003802412	SCV004609007	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-08	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 (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 234 of the FBN1 protein (p.Gly234Cys). This variant disrupts the p.Gly234 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004783115	SCV005394133	likely pathogenic	Familial aortopathy	2024-09-03	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.700G>T (p.Gly234Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 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 (PMID: 1301946). Therefore, this substitution resulting in the creation of a novel cysteine residue may disrupt the structure of the FBN1 protein, affecting its function. The variant was absent in 251282 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.700G>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2951150). Additionally, a different missense variant affecting the same codon, c.701G>T (p.G234V), has been reported in association with Marfan syndrome and aortic dissection in the literature and was also found to segregate with disease (PMIDs: 25370960, 28973303) Based on the evidence outlined above, the variant was classified as likely pathogenic.