Submissions for variant NM_000138.5(FBN1):c.1420T>G (p.Cys474Gly)

dbSNP: rs1555400380

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	RCV004767423	SCV000695453	uncertain significance	not specified	2024-08-12	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1420T>G (p.Cys474Gly) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Missense mutations affecting or creating cysteine residues are listed among the criteria for a causal FBN1 mutation when identified as de novo (with proven paternity) in the revised Ghent criteria for the diagnosis of Marfan and related conditions (Loeys 2010). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251218 control chromosomes. To our knowledge, no occurrence of c.1420T>G in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 495555). Based on the evidence outlined above, until the de novo origin of this variant is unequivocally confirmed, the variant is classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003767325	SCV004594502	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-06-03	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Cys474 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10721679, 16571647, 16905551, 17701892, 19349279). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 495555). 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 cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 474 of the FBN1 protein (p.Cys474Gly).