Submissions for variant NM_000138.5(FBN1):c.1570dup (p.Thr524fs)

dbSNP: rs1555400274

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497892	SCV000589612	pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26582918, 19293843, 30675029)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539674	SCV000627838	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr524Asnfs*9) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Marfan syndrome (PMID: 19293843). ClinVar contains an entry for this variant (Variation ID: 431982). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	RCV000766241	SCV000897656	pathogenic	Marfan syndrome	2018-11-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000497892	SCV003800232	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing	The FBN1 c.1570dupA; p.Thr524AsnfsTer9 variant (rs1555400274) is reported in the literature in at least two individuals diagnosed with Marfan syndrome (Renner 2019, Stheneur 2009) and is reported as pathogenic by two sources in the ClinVar database (Variation ID: 431982). This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is classified as pathogenic. References: Renner S et al. Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients. Genet Med. 2019 Aug;21(8):1832-1841. PMID: 30675029. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. PMID: 19293843.