Submissions for variant NM_000138.5(FBN1):c.1087G>A (p.Gly363Ser)

gnomAD frequency: 0.00004  dbSNP: rs363855

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699330	SCV000828036	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 363 of the FBN1 protein (p.Gly363Ser). This variant is present in population databases (rs363855, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 576755). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001182974	SCV001348613	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 363 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 been identified in 11/282662 chromosomes 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258190	SCV001435079	uncertain significance	Marfan syndrome		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001508392	SCV001714517	uncertain significance	not provided	2019-06-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001508392	SCV003836904	uncertain significance	not provided	2023-08-16	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003) Collod-Beroud G et al. (2003) Hum Mutat 22 (3):199-208 (PMID: 12938084); This variant is associated with the following publications: (PMID: 19370756)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001182974	SCV003837688	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-11-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001258190	SCV004823084	uncertain significance	Marfan syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 363 of the FBN1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 11/282662 chromosomes 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.