Submissions for variant NM_000138.5(FBN1):c.5513G>A (p.Gly1838Asp)

dbSNP: rs78970689

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181546	SCV000233849	pathogenic	not provided	2014-05-07	criteria provided, single submitter	clinical testing	p.Gly1838Asp (GGC>GAC): c.5513 G>A in exon 45 of the FBN1 gene (NM_000138.4)While the G1838D mutation in the FBN1 gene has not been reported to our knowledge, a mutation affecting this same residue, G1838C, has been reported in association with Marfan syndrome (Ganesh A et al., 2006). Additionally, mutations in nearby residues (C1835F, C1835Y, P1837S, C1847W, C1847R) have been reported in association with Marfan syndrome, further supporting the functional importance of this residue and this region of the protein. G1838D results in 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 conserved across species. In silico analysis predicts this mutation is damaging to the protein structure/function. Furthermore, G1838D 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 summary, G1838D in the FBN1 gene is interpreted as a likely disease-causing mutation. The variant is found in TAAD panel(s).
Invitae	RCV000632002	SCV000753105	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-12-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly1838 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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: 200065). This missense change has been observed in individuals with Marfan syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1838 of the FBN1 protein (p.Gly1838Asp).
Revvity Omics, Revvity	RCV000181546	SCV003833996	uncertain significance	not provided	2021-12-09	criteria provided, single submitter	clinical testing