Submissions for variant NM_000138.5(FBN1):c.4337A>G (p.Asp1446Gly)

dbSNP: rs397515806

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001185399	SCV001351597	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces the conserved aspartic acid with glycine at codon 1446 in the calcium-binding EGF-like motif 25 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual suspected of having Marfan syndrome (PMID: 25652356). This proband showed cardiovascular involvement with unknown Ghent criteria and no family history of Marfan syndrome. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001235478	SCV001408165	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-03-13	criteria provided, single submitter	clinical testing	An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. This variant disrupts the p.Asp1446 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 25652356, 25907466), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 924199). This missense change has been observed in individuals with clinical features of Marfan syndrome and/or FBN1-related conditions (PMID: 25652356, 33824467; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1446 of the FBN1 protein (p.Asp1446Gly).
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374758	SCV001439539	uncertain significance	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003444780	SCV004171725	likely pathogenic	Marfan syndrome	2022-05-22	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in two individuals with aortic disease (Baudhuin 2015 PMID: 25652356; Li 2021 PMID: 33824467). This variant is not present in large control databases but is present in ClinVar (Variation ID: 924199). Evolutionary conservation and computational predictive tools suggest that this variant impacts the protein. This variant is located within the consensus binding sequence in a calcium-binding epidermal growth factor (cbEGF)-like domain and may impair protein folding or stabilization (Jensen 2005 PMID: 15649891). Other variants at this same position have been reported in association with Marfan syndrome or aortic disease (p.Asp1446Val, p.Asp1446Asn). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Department of Laboratory Medicine and Genetics, Samsung Medical Center	RCV001185399	SCV005684882	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2025-01-02	no assertion criteria provided	clinical testing	The NM_000138.5:c.4337A>G is considered to be rare in the general population database (gnomAD v2.1.1). This variant is predicted to be deleterious by in-silico analysis (REVEL). This variant is located in functional domains and a different missense variant at the same residue is determined to be pathogenic (c.4336G>A, p.Asp1446Asn). This variant was found in a patient with suspected Marfan syndrome (PMID: 25652356; 33824467). This variant was found in a patient and her five family members showing aortic root dilatation or dissection (Samsung Medical Center internal data). According to the ClinGen guidance for PP1/BS4 and PP4 criteria (PMID: 38103548), PP1 with weighted strength was applied. In summary, this variant was classified as a pathogenic variant (PM1, PM5, PP1 with weighted strength, PP2, PP3, PS4_P, PM2_P).