Submissions for variant NM_000138.5(FBN1):c.2728+1G>C

dbSNP: rs794728322

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181678	SCV000233981	pathogenic	not provided	2014-09-29	criteria provided, single submitter	clinical testing	c.2728+1 G>C: IVS23+1 G>C in intron 23 of the FBN1 gene (NM_000138.4) Although the FBN1 mutation has not been reported as a disease- causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice donor site in intron 23 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the FBN1 gene have been reported in association with Marfan syndrome. In summary, c.2728+1 G>C in the FBN1 gene is interpreted as a disease-causing mutation.The variant is found in TAAD panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705129	SCV000834112	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2018-02-20	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 23 of the FBN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FBN1-related disease. ClinVar contains an entry for this variant (Variation ID: 200174). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). 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. A different variant affecting this nucleotide (c.2728+1G>A) has been reported in individuals with Marfan syndrome (PMID: 19293843, 22772377).
Ambry Genetics	RCV002426872	SCV002743629	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-04-16	criteria provided, single submitter	clinical testing	The c.2728+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 22 of the FBN1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in individuals with Marfan syndrome (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.