Submissions for variant NM_000138.5(FBN1):c.1625A>G (p.Asn542Ser)

dbSNP: rs963564435

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001190762	SCV001358346	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 542 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 been reported in an individual affected with bicuspid aortic valve (PMID: 30255099). This variant has been identified in 1/251274 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508391	SCV001714515	uncertain significance	not provided	2020-09-25	criteria provided, single submitter	clinical testing
GeneDx	RCV001508391	SCV001988034	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	Reported in cis with FBN1 p.(K2460R) in a patient with bicuspid aortic valve, TAAD, and additional connective tissue features who also harbored variants in TGFBR3, NOTCH1, and LTBP1; the FBN1 variants segregated with systemic connective tissue features in his mother, and the TGFBR3 variant segregated with aortic root dilation in his father and siblings (Sticchi et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; 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); This variant is associated with the following publications: (PMID: 35451555, 12938084, 30255099)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002560093	SCV003243580	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004010457	SCV004823038	uncertain significance	Marfan syndrome	2023-12-18	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the calcium-binding EGF-like motif 8 of the FBN1 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with bicuspid aortic valve (PMID: 30255099). This variant has been identified in 1/246060 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.