ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1285C>T (p.Arg429Ter) (rs112645512)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000253662 SCV000319232 pathogenic Cardiovascular phenotype 2017-02-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000312925 SCV000329345 pathogenic not provided 2017-11-13 criteria provided, single submitter clinical testing The R429X pathogenic variant in the FBN1 gene has previously been reported in association with Marfan syndrome (MFS) (Rommel et al., 2002; Sakai et al., 2006; Attanasio et al., 2008; Magyar et al., 2009; Baudhuin et al., 2015). Rommel et al. (2002) first reported R429X in a 41 year-old man with a diagnosis of MFS based on a dilated ascending aorta requiring surgical replacement and reconstruction of the aortic valve, mitral valve prolapse/insufficiency, and bilateral ectopia lentis. His 17 year-old son, who had a Marfanoid body habitus, scoliosis, and slight dilatation of the ascending aorta, was shown to be heterozygous for this variant (Rommel et al., 2002). The R429X variant was also identified in a 35 year-old male who did not meet Ghent criteria for MFS but satisfied minor criteria for skeletal, pulmonary, and skin involvement and major criteria for cardiovascular involvement (Sakai et al., 2006), in a 35 year-old female diagnosed with MFS who had skeletal, ocular and cardiovascular involvement (Magyar et al., 2009), in a 22 year-old female who fulfilled Ghent criteria for a diagnosis of MFS (Attanasio et al., 2008), and in a 37 y/o female with a history of aortic dissection and aortic valve prolapse who also fulfilled Ghent criteria for a diagnosis of MFS (Baudhuin et al., 2014). Additionally, the R429X variant has been identified in other unrelated individuals referred for MFS genetic testing at GeneDx. Collectively, this variant was absent from 300 published control chromosomes (Sakai et al., 2006; Attanasio et al., 2008) and was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R429X is predicted to cause loss of normal protein function either by protein truncation or nonsensemediated mRNA decay. Furthermore, many other downstream nonsense variants in the FBN1 gene have been reported in HGMD in association with Marfan syndrome (Stenson et al., 2014). In summary, R429X in the FBN1 gene is interpreted as a pathogenic variant.
Invitae RCV000791401 SCV000544841 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg429*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Marfan syndrome or suspected Marfan syndrome (PMID: 12402346, 18435798, 16835936, 27234404, 19618372). ClinVar contains an entry for this variant (Variation ID: 180351). Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc RCV000157224 SCV000781329 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157224 SCV000206948 pathogenic Marfan syndrome 2014-05-09 no assertion criteria provided clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000157224 SCV000786741 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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