Submissions for variant NM_000138.5(FBN1):c.7039_7040del (p.Met2347fs)

dbSNP: rs794728319

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181674	SCV000233977	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 29357934, 11826022, 25101912, 27112580, 17627385, 19863550, 26272055, 17657824, 19618372, 18435798, 29543232, 33436942, 32679894, 34008892, 26621581)
Blueprint Genetics	RCV000208062	SCV000263920	pathogenic	Marfan syndrome	2015-08-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524503	SCV000283647	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met2347Valfs*19) 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 individuals with Marfan syndrome (PMID: 11826022, 17627385, 19618372, 26272055, 26621581). ClinVar contains an entry for this variant (Variation ID: 200171). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000613882	SCV000738824	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-07-07	criteria provided, single submitter	clinical testing	The c.7039_7040delAT pathogenic mutation, located in coding exon 57 of the FBN1 gene, results from a deletion of two nucleotides at nucleotide positions 7039 to 7040, causing a translational frameshift with a predicted alternate stop codon (p.M2347Vfs*19). This alteration has been described in multiple individuals with Marfan syndrome or related phenotypes (Körkkö J et al. J Med Genet. 2002 ;39:34-41; Howarth R et al. Genet Test. 2007;11:146-52; Comeglio P et al. Hum Mutat. 2007;28:928; Attanasio M et al. Clin Genet. 2008 ;74:39-46; Magyar I et al. Hum Mutat. 2009;30:1355-64; Yoo EH et al. Clin Genet. 2010;77:177-82; Regalado ES et al. Clin Genet. 2016 ;89:719-23; Guo J et al. Sci Rep. 2015;5:13115; Somers AE et al. Am J Med Genet A. 2016;170:1786-90). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000208062	SCV000781410	pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000181674	SCV000885431	pathogenic	not provided	2017-09-16	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000208062	SCV000928336	pathogenic	Marfan syndrome	2018-01-04	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192804	SCV001361164	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2019-02-25	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7039_7040delAT (p.Met2347ValfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 245612 control chromosomes (gnomAD). c.7039_7040delAT has been reported in the literature in multiple individuals affected with Marfan Syndrome (Korkko_2002, Attanasio_2008, Comeglio_2007, Yoo_2010, Baudhuin_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratoire Génétique Moléculaire, CHRU TOURS	RCV000181674	SCV001760720	pathogenic	not provided	2020-09-23	criteria provided, single submitter	clinical testing
3billion	RCV001775090	SCV002012050	pathogenic	Weill-Marchesani syndrome 2, dominant	2021-10-02	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000200171.11). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centre of Medical Genetics, University of Antwerp	RCV000208062	SCV002025431	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS1, PP4 or PM2, PVS1, PP1, PP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000613882	SCV002042012	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-05-14	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV000208062	SCV002577937	pathogenic	Marfan syndrome	2021-12-20	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PP3,PP5
Lifecell International Pvt. Ltd	RCV000208062	SCV003924076	pathogenic	Marfan syndrome		criteria provided, single submitter	clinical testing	A Heterozygous Frameshift variant c.7039_7040delAT in Exon 58 of the FBN1 gene that results in the amino acid substitution p.Met2347fs*19 was identified. The observed variant novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 200171). This variant has previously been reported for Marfan syndrome (Comeglio P et al., 2007). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000613882	SCV000731223	pathogenic	Familial thoracic aortic aneurysm and aortic dissection		no assertion criteria provided	research
Center for Medical Genetics Ghent, University of Ghent	RCV000208062	SCV000787293	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000208062	SCV000787294	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755190	SCV000883019	likely pathogenic	Congenital aneurysm of ascending aorta; Acute aortic dissection	2016-01-20	no assertion criteria provided	research