ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.8326C>T (p.Arg2776Ter) (rs137854466)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181630 SCV000233933 pathogenic not provided 2018-06-26 criteria provided, single submitter clinical testing The R2776X variant in the FBN1 gene has been reported previously in individuals with Marfan syndrome, including one individual in which this variant apparently occurred de novo (Hayward et al., 1997; Stheneur et al., 2009). The R2776X variant is predicted to cause loss of normal protein function by loss of the last 96 residues (Lonnqvist et al., 1998; Ritty et al., 1999; Jensen et al., 2014). Functional studies suggest that the R2776X variant results in intra-cellular retention of the protein (Jensen et al., 2014). Other nonsense variants in the FBN1 gene, including several that occur downstream, have been reported in the Human Gene Mutation Database in association with TAAD-related disorders (Stenson et al., 2014). Furthermore, the R2776X pathogenic variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, R2776X in the FBN1 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000249596 SCV000320556 pathogenic Cardiovascular phenotype 2017-06-29 criteria provided, single submitter clinical testing The p.R2776* pathogenic mutation (also known as c.8326C>T), located in coding exon 65 of the FBN1 gene, results from a C to T substitution at nucleotide position 8326. This changes the amino acid from an arginine to a stop codon within coding exon 65. In one study, this alteration (referred to as p.R1878*, c.5632C>T) was detected in a female patient with Marfan syndrome (MFS) and her son with less severe clinical manifestations (Hayward C et al. Hum Mutat. 1994;3(2):159-62). This alteration has also been identified in other patients with MFS and is in the fibulin-like domain (Körkkö J et al. J Med Genet. 2002;39(1):34-41; Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000181630 SCV000340055 pathogenic not provided 2016-03-01 criteria provided, single submitter clinical testing
Invitae RCV000631918 SCV000753021 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-03-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the FBN1 gene (p.Arg2776*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 96 amino acids of the FBN1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with FBN-1 related conditions (PMID: 7911051, 9338581, 11826022). ClinVar contains an entry for this variant (Variation ID: 16439). Several different truncating variants downstream of this variant (p.Leu2854Profs*9, p.Gln2830*, p.Leu2854Profs*9) have been determined to be pathogenic (Invitae). This suggests that deletion of this region of the FBN1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations RCV000017901 SCV000930047 pathogenic Marfan syndrome 2019-07-19 criteria provided, single submitter clinical testing At our clinical center The p.R2776* variant was found in one family and one unrelated individual. This variant present in variouas individual studies reported by other submitters (ClinVar entry - Variation ID:16439), as well as present in population studies (C=0.00001 (1/121406, ExAC)). Functional study of the variant (PMID: 24982166) shows its pathogenic mechanism by linkage of the immature monomers, thus it behaves as a dominant-negative mutation, disrupting not only the mutant protein, but the normal one, which is synthesized from the unchanged allele.
Department of Vascular Biology,Beijing Anzhen Hospital RCV001374806 SCV001439507 likely pathogenic Isolated thoracic aortic aneurysm 2018-09-01 criteria provided, single submitter research
OMIM RCV000017901 SCV000038180 pathogenic Marfan syndrome 1994-01-01 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000017901 SCV000052447 pathogenic Marfan syndrome 2015-04-09 no assertion criteria provided clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000017901 SCV000787408 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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