Submissions for variant NM_000138.5(FBN1):c.3026C>G (p.Pro1009Arg)

gnomAD frequency: 0.00002  dbSNP: rs148076256

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541723	SCV000627879	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1009 of the FBN1 protein (p.Pro1009Arg). This variant is present in population databases (rs148076256, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with FBN1-related conditions (PMID: 27112580, 28087566; Invitae). ClinVar contains an entry for this variant (Variation ID: 36061). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590133	SCV000695502	uncertain significance	not specified	2017-05-02	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.3026C>G (p.Pro1009Arg) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within a TB domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000742 (9/121338 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125). The variant was detected in a Marfan syndrome patient who met the revised Ghent criteria (Somers_Am J Med Genet A_2016). However, co-occurrence and cosegregation data were not provided. Functional studies have not been performed on the variant to date. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000777737	SCV000913696	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 1009 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 two individuals affected with Marfan syndrome or related conditions (PMID: 27112580, ClinVar SCV000627879.3), as well as in an individual affected with dilated cardiomyopathy with no indication of Marfan syndrome (PMID: 28087566). This variant has also been identified in 17/251444 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	RCV001558963	SCV001781010	uncertain significance	not provided	2021-09-02	criteria provided, single submitter	clinical testing	Identified in a patient with Marfan syndrome, but also in a patient with dilated cardiomyopathy and no features indicative of Marfan syndrome (Somers et al., 2016; Seidelmann et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Does not affect a cysteine residue within a calcium-binding EGF-like 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); This variant is associated with the following publications: (PMID: 27906200, 27112580, 28087566)
Ambry Genetics	RCV000777737	SCV002753151	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-12-18	criteria provided, single submitter	clinical testing	The p.P1009R variant (also known as c.3026C>G), located in coding exon 24 of the FBN1 gene, results from a C to G substitution at nucleotide position 3026. The proline at codon 1009 is replaced by arginine, an amino acid with dissimilar properties, and in located in the TGFBP #03 domain. This variant was reported in an individual with Marfan syndrome (MFS), as well as in another individual with dilated cardiomyopathy and no reported MFS findings (Somers AE et al. Am. J. Med. Genet. A, 2016 07;170:1786-90; Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10:[Epub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002477019	SCV002776852	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	2021-12-07	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002477019	SCV003919943	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	2021-03-30	criteria provided, single submitter	clinical testing	FBN1 NM_000138.4 exon 25 p.Pro1009Arg (c.3026C>G): This variant has been reported in the literature in one individual meeting Ghent criteria for Marfan syndrome (Somers 2016 PMID:27112580) and in one individual with dilated cardiomyopathy but no reported features of Marfan syndrome (Seidelmann 2017 PMID: 28087566). This variant is present in approximately 0.009% (10/111672) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-48782104-G-C) and is also present in ClinVar (Variation ID:36061). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health	RCV003996125	SCV004814839	uncertain significance	Marfan syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 1009 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 two individuals affected with Marfan syndrome or related conditions (PMID: 27112580, ClinVar SCV000627879.3), as well as in an individual affected with dilated cardiomyopathy with no indication of Marfan syndrome (PMID: 28087566). This variant has also been identified in 17/251444 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.
GenomeConnect, ClinGen	RCV003227610	SCV003925465	not provided	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Weill-Marchesani syndrome 2, dominant; Familial thoracic aortic aneurysm and aortic dissection		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-24-2019 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.