Submissions for variant NM_000138.5(FBN1):c.442+1G>A

gnomAD frequency: 0.00003  dbSNP: rs868403743

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658447	SCV000780219	likely pathogenic	not provided	2023-09-15	criteria provided, single submitter	clinical testing	Identified in one individual with sudden cardiac death at 80 years of age who had a history atherosclerotic cardiovascular disease, but detailed clinical information was not provided (Khera et al., 2019); Canonical splice site variant demonstrated to result in an in-frame loss of the adjacent exon (Wai et al., 2020) in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32123317, 31727422, 33087929)
Invitae	RCV000807677	SCV000947743	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-09-04	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 546550). Disruption of this splice site has been observed in individual(s) with sudden cardiac death (PMID: 31727422). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 5 of the FBN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
Fulgent Genetics, Fulgent Genetics	RCV002485499	SCV002796854	likely pathogenic	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-10-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003528217	SCV004357500	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-06-21	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 5 of the FBN1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A RNA study with blood samples from carriers has shown that this variant causes an in-frame skipping of exon 5 and replaces it with a threonine residue (c.347_442del, p.Ile116_Pro148delinsThr), creating a shortened protein product lacking the EGF-like motif 2 (a.a. 115 - 146). This variant has been reported in an individual affected with atherosclerotic cardiovascular disease and sudden cardiac death (PMID: 31727422). This variant has been identified in 1/282556 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of FBN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000658447	SCV004848125	uncertain significance	not provided	2019-09-11	criteria provided, single submitter	clinical testing	The c.442+1G>A variant in FBN1 has been identified in 1 individual with Marfan syndrome who also had an additional pathogenic variant in FBN1 that segregated with disease in 2 affected siblings (Invitae pers. comm.). It has also been identified in 1/128936 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported by other clinical laboratories in ClinVar (Variation ID #546550). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. However, exon 4 is in frame and consists of only 96 base pairs and encodes less than 10% of the FBN1 protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, BP2.