Submissions for variant NM_000138.5(FBN1):c.229G>A (p.Gly77Arg)

dbSNP: rs794728290

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181641	SCV000233944	uncertain significance	not provided	2014-05-16	criteria provided, single submitter	clinical testing	p.Gly77Arg (GGA>AGA) c.229 G>A (NM_000138.4) The G77R variant has not been published as a mutation or as a benign polymorphism to our knowledge. The G77R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the G77R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is completely conserved across species. In silico analysis predicts this variant is possibly damaging to the protein structure/function. Furthermore, missense mutations in nearby residues (W71R, C80Y, C80G, C80R) have been reported in association with Marfan syndrome, supporting the functional importance of this region of the protein.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in TAAD panel(s).
Invitae	RCV000812218	SCV000952525	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-13	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 77 of the FBN1 protein (p.Gly77Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 32939518; Invitae). ClinVar contains an entry for this variant (Variation ID: 200140). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002444730	SCV002734837	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-12-07	criteria provided, single submitter	clinical testing	The p.G77R variant (also known as c.229G>A), located in coding exon 2 of the FBN1 gene, results from a G to A substitution at nucleotide position 229. The glycine at codon 77 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a subject with features of Marfan syndrome (Yalcintepe S et al. Glob Med Genet, 2020 Aug;7:68-71). 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.
Genetics and Molecular Pathology, SA Pathology	RCV002466462	SCV002761859	likely pathogenic	Marfan syndrome	2021-01-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002485197	SCV002778834	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	2021-11-08	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535800	SCV001749970	not provided	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Familial thoracic aortic aneurysm and aortic dissection		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-16-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.