Submissions for variant NM_000138.5(FBN1):c.6155G>C (p.Arg2052Thr)

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	RCV004587686	SCV005076172	uncertain significance	not specified	2024-04-15	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.6155G>C (p.Arg2052Thr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251032 control chromosomes (gnomAD). 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.6155G>C in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005216264	SCV005856793	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 2052 of the FBN1 protein (p.Arg2052Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FBN1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.