Submissions for variant NM_000138.5(FBN1):c.7167_7168del (p.Cys2390fs)

dbSNP: rs397515846

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000035265	SCV003933666	pathogenic	Marfan syndrome	2023-06-15	reviewed by expert panel	curation	The NM_00138 c.7165_7166, is a frameshift variant in FBN1 is predicted to result in a premature stop codon at position 2404. It is expected to cause a shift in the reading frame and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with a diagnosis of Marfan syndrome, with thoracic aortic aneurysm, skeletal features, which is a highly specific phenotype for Marfan syndrome (internal data) (PP4). This variant, also described as c.7167_7169del2 or p.Leu2389fsX16 using alternate nomenclature, has also been described in three other probands with a clinical diagnosis of Marfan syndrome (PMID 25907466, 17657824, internal data) and in three probands suspected of having Marfan syndrome (PMID 24793577, 14695540, internal data) (PS4). The variant has been identified as a de novo occurrence in an individual with a phenotype consistent with the gene but not highly specific (PM6_Supportive). This variant has been reported 5 times in ClinVar as pathogenic (Variantion ID: 42420). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PS4, PM6_Supportive, PM2_Supportive, PP4
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035265	SCV000058912	pathogenic	Marfan syndrome	2010-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000181675	SCV000233978	pathogenic	not provided	2014-03-12	criteria provided, single submitter	clinical testing	The c.7167_7168delCT mutation in the FBN1 gene has been reported in one individual with Marfan or Marfan-like syndrome (reported as c.7167_7169del2 or p.Leu2389fsX16, using alternate nomenclature; Biggin et al., 2004). This individual had a positive wrist and thumb sign, joint hypermobility, highly arched palate with dental crowding, characteristic facial appearance, dilated aorta, and mitral valve prolapse. The c.7167_7168delCT mutation involves the latent transforming growth factor b1 binding protein (LTBP) domain of the FBN1 gene (Biggin et al., 2004). Additionally, c.7167_7168delCT wasnot observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This mutation causes a shift in reading frame starting at codon Cysteine 2390, changing it to a Serine, and creating a premature stop codon at position 15 of the new reading frame, denoted p.Cys2390SerfsX15. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the FBN1 gene have been reported in association with Marfan syndrome. In summary, c.7167_7168delCT in the FBN1 gene is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589510	SCV000695596	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2016-04-29	criteria provided, single submitter	clinical testing	Variant summary: The c.7167_7168delCT variant results in a premature termination codon, predicted to cause a truncated or absent FBN1 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.7180C>T, p.Arg2394X; c.8326C>T, p.Arg2776X). The variant is absent from the large, broad ExAC control population. The variant has been reported in multiple affected MFS patients from the literature and has been reported by multiple reputable clinical labs as "Pathogenic". Taken together, this variant has been classified as a Pathogenic.
Centre of Medical Genetics, University of Antwerp	RCV000035265	SCV002025436	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS1, PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764666	SCV004570896	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys2390Serfs*15) 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 clinical features of Marfan syndrome (PMID: 14695540). This variant is also known as c.7167_7169del2 (p.Leu2389fsX16). ClinVar contains an entry for this variant (Variation ID: 42420). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000035265	SCV000787305	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing