Submissions for variant NM_000138.5(FBN1):c.4460A>G (p.Asp1487Gly)

dbSNP: rs1555397216

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632009	SCV000753112	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2020-06-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp1487 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 21542060, Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 30838813, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 527205). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 1487 of the FBN1 protein (p.Asp1487Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470939	SCV002767125	pathogenic	Marfan syndrome	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an aspartic acid to a glycine (exon 37). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is very highly conserved with a moderate amino acid change. (P) 0508 – This variant is the last base of the exon, however in silico predictions for abnormal splicing are conflicting. (N) 0600 - Variant is located in an annotated domain or motif (Calcium-binding EGF domain; PDB). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. Two different variants in the same codon resulting in a change to alanine and asparagine have been shown to cause Marfan syndrome (ClinVar, PMID: 21542060). However the change to asparagine has also been reported as VUS in ClinVar. (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with Marfan syndrome (ClinVar, PMID: 30838813). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed) (VCGS #20G002071, 20G002072). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
GeneDx	RCV004721502	SCV005327731	likely pathogenic	not provided	2023-12-29	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 20591885, 30838813)