ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4567C>T (p.Arg1523Ter)

dbSNP: rs397515812
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000035205 SCV000058848 pathogenic Marfan syndrome 2018-04-20 criteria provided, single submitter clinical testing The p.Arg1523X variant in FBN1 has been reported in at least 6 individuals with clinical features of Marfan syndrome (Vandersteen 2013, Schrijver 2002, Baudhuin 2014, Soylen 2009, Youil 2000, LMM data) and has also been reported by other cl inical laboratories in ClinVar (Variation ID: 42365). It has been identified in 1/245856 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs397515812). This nonsense variant leads to a prematur e termination codon at position 1523, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FBN1 gene is an establis hed disease mechanism in individuals with Marfan syndrome. In summary, this vari ant meets criteria to be classified as pathogenic for Marfan syndrome in an auto somal dominant manner based upon presence in multiple affected individuals and t he predicted impact on the protein. ACMG/AMP Criteria applied: PVS1, PS4.
Invitae RCV000539432 SCV000627921 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-01-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1523*) 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 present in population databases (rs397515812, gnomAD no frequency). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 10874320, 12068374). ClinVar contains an entry for this variant (Variation ID: 42365). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000579083 SCV000680640 pathogenic not provided 2023-01-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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: 10874320, 25525159, 12068374, 31279664, 31447099, 23505274, 19159394, 31325479, 31730815, 34498425, 35943490, 19012347, 25101912, 33824467)
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000035205 SCV000781374 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000770665 SCV000902124 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2019-05-27 criteria provided, single submitter clinical testing
Department of Vascular Biology, Beijing Anzhen Hospital RCV001374850 SCV001439534 likely pathogenic Isolated thoracic aortic aneurysm 2018-09-01 criteria provided, single submitter research
Ambry Genetics RCV000770665 SCV002637287 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-12-16 criteria provided, single submitter clinical testing The p.R1523* pathogenic mutation (also known as c.4567C>T), located in coding exon 36 of the FBN1 gene, results from a C to T substitution at nucleotide position 4567. This changes the amino acid from an arginine to a stop codon within coding exon 36. THis alteration has been reported in subjects with features of Marfan syndrome and has been reported as de novo (Youil R et al. Hum Mutat, 2000 Jul;16:92-3; Schrijver I et al. Am J Hum Genet, 2002 Aug;71:223-37; Rybczynski M et al. Am J Med Genet A, 2008 Dec;146A:3157-66; Söylen B et al. Clin Genet, 2009 Mar;75:265-70). In addition to the clinical data presented in the literature, 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 Medical Genetics Ghent, University of Ghent RCV000035205 SCV000787077 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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