Submissions for variant NM_000138.5(FBN1):c.457G>A (p.Gly153Ser)

dbSNP: rs995711019

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170331	SCV001332902	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-10-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001296597	SCV001485566	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-10	criteria provided, single submitter	clinical testing	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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 915553). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 153 of the FBN1 protein (p.Gly153Ser).
All of Us Research Program, National Institutes of Health	RCV004000270	SCV004825764	uncertain significance	Marfan syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 153 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.