Submissions for variant NM_000138.5(FBN1):c.8543_8544del (p.Lys2848fs)

dbSNP: rs794728323

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599311	SCV000710080	pathogenic	not provided	2017-11-02	criteria provided, single submitter	clinical testing	Although the c.8543_8544delAA pathogenic variant in the FBN1 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon lysine 2848, changing it to an isoleucine, and creating a premature stop codon at position two of the new reading frame, denoted p.K2848IfsX2. This pathogenic variant is expected to result in an abnormal, truncated protein product. Many other frameshift variants in the FBN1 gene have been reported in Human Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, c.8543_8544delAA has not been observed in large population cohorts (Lek et al., 2016). In summary, c.8543_8544delAA in the FBN1 gene is interpreted as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868003	SCV002232514	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-08-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FBN1 protein in which other variant(s) (p.Gln2867*) have been determined to be pathogenic (PMID: 19293843). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 503785). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys2848Ilefs*2) in the FBN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the FBN1 protein.