Submissions for variant NM_000138.5(FBN1):c.4210G>A (p.Asp1404Asn)

dbSNP: rs794728220

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181512	SCV000233815	uncertain significance	not provided	2022-07-11	criteria provided, single submitter	clinical testing	Identified in individuals with Marfan syndrome in the published literature (PMID: 33059708); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20591885, 33059708)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852280	SCV002275810	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-06-11	criteria provided, single submitter	clinical testing	This variant disrupts the p.Asp1404 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9338581). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. Nucleotide substitutions within 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 disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This sequence change replaces aspartic acid with asparagine at codon 1404 of the FBN1 protein (p.Asp1404Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant also falls at the last nucleotide of exon 34, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 200040). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").