ClinVar

Description

Variant summary: FBN1 c.3146G>A (p.Gly1049Asp) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3146G>A has been reported in the literature as a likely pathogenic variant in an individual affected with Marfan Syndrome and as a VUS in an individual affected with isolated thoracic aortic aneurysm (example, Meester_2021, Li_2021). It has also been observed to segregate with features of Marfan disease among individual(s) from a family referred for Marfan testing at our laboratory. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33824467, 35058154). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.