Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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. |
Gene |
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, |
RCV000035205 | SCV000781374 | pathogenic | Marfan syndrome | 2016-11-01 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV000770665 | SCV000902124 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2019-05-27 | criteria provided, single submitter | clinical testing | |
Department of Vascular Biology, |
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, |
RCV000035205 | SCV000787077 | pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |