Submissions for variant NM_000138.5(FBN1):c.863A>G (p.Asp288Gly)

gnomAD frequency: 0.00001  dbSNP: rs565078451

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002313275	SCV000738922	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-09-01	criteria provided, single submitter	clinical testing	The p.D288G variant (also known as c.863A>G), located in coding exon 8 of the FBN1 gene, results from an A to G substitution at nucleotide position 863. The aspartic acid at codon 288 is replaced by glycine, an amino acid with similar properties, and is located in the cbEGF-like #02 domain. This change occurs in the first base pair of coding exon 8. This amino acid position is highly conserved in available vertebrate species. In addition, the amino acid change is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001039476	SCV001203008	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-02-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 288 of the FBN1 protein (p.Asp288Gly). This variant is present in population databases (rs565078451, gnomAD 0.008%). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 31098894). ClinVar contains an entry for this variant (Variation ID: 519791). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Fulgent Genetics, Fulgent Genetics	RCV002483730	SCV002788388	uncertain significance	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-10-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002313275	SCV004357484	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 288 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 been reported in an individual affected with Marfan syndrome (PMID: 31098894). This individual also carried a pathogenic covariant in the same gene but phase of these two FBN1 variants was unknown. This variant has been identified in 12/282652 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994049	SCV004813394	uncertain significance	not specified	2024-02-20	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.863A>G (p.Asp288Gly) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant alters a nucleotide in the exonic splice region of Exon 9. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.6e-05 in 251274 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.863A>G has been reported in the literature in cis with another missense (VUS-Possibly Pothogenic at our lab) in one individual affected with Marfan Syndrome (example, Li_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31098894). ClinVar contains an entry for this variant (Variation ID: 519791). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000664035	SCV004820648	uncertain significance	Marfan syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 288 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 been reported in an individual affected with Marfan syndrome (PMID: 31098894). This individual also carried a pathogenic covariant in the same gene but phase of these two FBN1 variants was unknown. This variant has been identified in 12/282652 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.
Center for Medical Genetics Ghent, University of Ghent	RCV000664035	SCV000787427	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000995350	SCV001740116	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000995350	SCV001970085	uncertain significance	not provided		no assertion criteria provided	clinical testing