Submissions for variant NM_000138.5(FBN1):c.6496G>A (p.Asp2166Asn)

dbSNP: rs794728252

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181570	SCV000233873	pathogenic	not provided	2012-10-25	criteria provided, single submitter	clinical testing	p.Asp2166Asn (GAT>AAT):c.6496 G>A in exon 53 of the FBN1 gene (NM_000138.4)The Asp2166Asn mutation in the FBN1 gene has been reported previously in one patient who met clinical diagnostic criteria for Marfan syndrome (Baetens M et al., 2011). This mutation is assumed to act as a splice site mutation due to its position at the exon border (Baetens M et al., 2011). Other mutations affecting nearby residues (Ala2160Pro, Asp2168Gly) have also been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Futhermore, the NHLBI ESP Exome Variant Server reports Asp2166Asn was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, Asp2166Asn in the FBN1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s).
Centre of Medical Genetics, University of Antwerp	RCV000663875	SCV002025397	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS6, PP4
Ambry Genetics	RCV003352796	SCV004078997	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-08-14	criteria provided, single submitter	clinical testing	The c.6496G>A variant (also known as p.D2166N), located in coding exon 52 of the FBN1 gene, results from a G to A substitution at nucleotide position 6496. The aspartic acid at codon 2166 asparagine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 52, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in individuals reported to have Marfan syndrome; however, in some cases, clinical details were limited and reported patients may overlap (Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Baetens M et al. Hum Mutat, 2011 Sep;32:1053-62; Meester JAN et al. Genet Med, 2022 May;24:1045-1053; Proost D et al. Hum Mutat, 2015 Aug;36:808-14). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003765116	SCV004570900	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2166 of the FBN1 protein (p.Asp2166Asn). This variant also falls at the last nucleotide of exon 53, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 200087). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 19293843, 21542060; Invitae). In at least one individual the variant was observed to be de novo.
Center for Medical Genetics Ghent, University of Ghent	RCV000663875	SCV000787239	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing