Submissions for variant NM_000138.5(FBN1):c.2953G>A (p.Gly985Arg)

dbSNP: rs794728199

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181473	SCV000233775	likely pathogenic	not provided	2024-08-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine or calcium-binding residue within an EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 34498425, 19002209, 19161152, 17627385, 16220557, 19863550, 24941995, 27479044, 24199744, 29907982, 33824467, 32123317, 33059708, 31098894, 34663891, 12938084, 11700157, 27611364, 37378398)
Ambry Genetics	RCV002310746	SCV000319440	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-07-11	criteria provided, single submitter	clinical testing	The p.G985R pathogenic mutation (also known as c.2953G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 2953. The glycine at codon 985 is replaced by arginine, an amino acid with dissimilar properties, and is located in the TGFBP #03 domain. This alteration has been identified in multiple individuals with classical Marfan syndrome and reported to co-segregate with disease (Loeys B et al. Arc Intern Med. 2001;161(20):2447-54; Howarth R et al. Genet. Test., 2007;11:146-52; Ware AL et al. Cardiovasc. Pathol. 2016 Jun;25:418-22). Another variant at the same codon, p.G985E (c.2954G>A), has been reported in individuals with classical Marfan syndrome (Collod-Béroud G et al. Am. J. Hum. Genet., 1999 Sep;65:917-21; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549578	SCV000627877	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 985 of the FBN1 protein (p.Gly985Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome or FBN1-related conditions (PMID: 11700157, 16220557, 17627385, 19863550, 24199744). ClinVar contains an entry for this variant (Variation ID: 200008). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586105	SCV000695500	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2017-06-21	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.2953G>A (p.Gly985Arg) missense variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools. This variant is located in TB domain and glycines in the FBN1 gene are implicated in correct domain-domain packing (Faive_2009). This variant is absent in 121470 control chromosomes (including ExAC). This variant has been reported in several MFS (classic as well as incomplete MFS) patients. In one family, this variant was found in three affected members with MFS or MFS-like syndrome but not in five unaffected members, indicating cosegregation with disease (Howarth_2007). In two other families, probands affected with classic MFS and two first-degree relatives in each family carried the variant; however affected status of the family members was not clearly indicated (Ware_2016). In contrast to the pathogenic outcome from these three families, a study reclassified this variant to benign from family segregation analysis (Yang_2016). However, genotypic and phenotypic details of family members were not provided, limiting independent evaluation of the evidences. Two clinical diagnostic laboratories (via ClinVar) have classified this variant as likely pathogenic (one has noted the finding of Yang_2016). Another missense change at the same residue G985E has also been reported in a patient with MFS, suggesting that Gly985 codon could be mutational hot-spot. Based on the currently available data, this variant is classified as likely pathogenic.
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374767	SCV001439548	likely pathogenic	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV002310746	SCV004240570	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-02-08	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000663591	SCV000786905	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing