Submissions for variant NM_000138.5(FBN1):c.1158C>G (p.Asn386Lys)

dbSNP: rs368737502

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001188119	SCV000318728	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2016-04-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631989	SCV000753092	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-12-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188119	SCV001355092	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 386 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-associated thoracic aortic aneurysm (PMID: 28659821). This variant has been identified in 15/249668 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.
GeneDx	RCV001660387	SCV001872880	uncertain significance	not provided	2021-06-10	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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27535533)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001188119	SCV003838363	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-02-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999026	SCV004823078	uncertain significance	Marfan syndrome	2024-08-30	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 386 of the FBN1 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. 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-associated thoracic aortic aneurysm (PMID: 28659821). This variant has been identified in 15/249668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.