Submissions for variant NM_000138.5(FBN1):c.7663G>A (p.Gly2555Arg)

dbSNP: rs1566891655

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687097	SCV000814648	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-07-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly2555 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17657824, 19293843). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 567107). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 28973303; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2555 of the FBN1 protein (p.Gly2555Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193503	SCV001362388	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2019-02-11	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7663G>A (p.Gly2555Arg) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 114338 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7663G>A has been reported in the literature in an individual affected with Marfan Syndrome and suggested to be a de novo occurrence. The patient's unaffected siblings and mother were genotyped and did not carry the variant. In addition, another variant affecting the same codon p.G2555V has been reported in at least 3 pts presenting with classical MFS. Other missense FBN1 variants nearby, p.R2554W, p.R2554Q, p.T2561P, have been reported in association with MFS, indicating this region could be important for proper FBN1 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001551561	SCV001772090	likely pathogenic	not provided	2024-04-23	criteria provided, single submitter	clinical testing	Reported in a patient with non-syndromic aortic aneurysm and an increased arm span to height ratio; however no additional clinical details or segregation data are available (PMID: 28973303); 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; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding 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: 17657824, 19293843, 12938084, 28973303)
Ambry Genetics	RCV002388203	SCV002669439	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-07-05	criteria provided, single submitter	clinical testing	The p.G2555R pathogenic mutation (also known as c.7663G>A), located in coding exon 61 of the FBN1 gene, results from a G to A substitution at nucleotide position 7663. The glycine at codon 2555 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in subjects with a suspected diagnosis of Marfan syndrome (Tan L et al. Hum Mol Genet, 2017 12;26:4814-4822; GeneDx pers. comm.). This variant has also been reported as de novo in a proband with aortic root dilation and spondylolisthesis (GeneDx pers. comm.). Another alteration at the same codon, p.G2555V (c.7664G>T), has been reported in individuals with clincal features of Marfan syndrome (Comeglio P et al. Hum Mutat, 2007 Sep;28:928). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
All of Us Research Program, National Institutes of Health	RCV004004260	SCV004828397	likely pathogenic	Marfan syndrome	2023-07-08	criteria provided, single submitter	clinical testing	The c.7663G>A (p.Gly2555Arg) variant of the FBN1 gene has been reported in the literature in one individual with non syndromic aortic dissection (PMID: 28973303). The variant was not detected in the patient's unaffected siblings and mother while the father?s DNA was unavailable for testing (PMID: 28973303). In-silico computational prediction tools suggest that the p.Gly2555Arg variant may have deleterious effect on the protein function (REVEL score: 0.907). This variant is absent in the general population database gnomAD. Another amino acid substitution at the same position (p.Gly2555Val) has been classified as pathogenic by two ClinVar submitters (ClinVar ID: 572714). Therefore, the c.7663G>A (p.Gly2555Arg) variant in FBN1 is classified as likely pathogenic.