Submissions for variant NM_000138.5(FBN1):c.3173G>T (p.Gly1058Val)

dbSNP: rs794728202

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181480	SCV000233783	pathogenic	not provided	2014-08-18	criteria provided, single submitter	clinical testing	p.Gly1058Val (GGC>GTC): c.3173 G>T in exon 26 of the FBN1 gene (NM_000138.4)The G1058V mutation in the FBN1 gene has been previously reported in one individual with Marfan syndrome in the Universal Mutation Database (Beroud C et al., 2000), however no clinical description was provided. Another missense variant in the same residue (G1058D) has been reported in a 23-year old female patient with aortic root dilation, ectopia lentis, and lumbo-sacral dural ectasia consistent with Marfan syndrome (Arbustini et al., 2005). G1058V results in a conservative amino acid substitution of Glycine at a position that is conserved across species. Mutations in nearby residues (C1053R, C1055G, S1063C, C1068G) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the G1058V mutation was not observed inapproximately 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, G1058V in the FBN1 gene is interpreted as a likely disease-causing mutation. The variant is found in TAAD panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517771	SCV003442943	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-04-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly1058 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16222657; Invitae). 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: 200013). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 27160103; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1058 of the FBN1 protein (p.Gly1058Val).