ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.8148C>G (p.Tyr2716Ter)

dbSNP: rs112642323
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208411 SCV000263913 likely pathogenic Marfan syndrome 2015-11-20 criteria provided, single submitter clinical testing
Centre of Medical Genetics, University of Antwerp RCV000208411 SCV002025474 pathogenic Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PVS1, PP4
Ambry Genetics RCV002415877 SCV002679523 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-08-11 criteria provided, single submitter clinical testing The p.Y2716* pathogenic mutation (also known as c.8148C>G), located in coding exon 64 of the FBN1 gene, results from a C to G substitution at nucleotide position 8148. This changes the amino acid from a tyrosine to a stop codon within coding exon 64. A different nucleotide change (c.8147dupA) resulting in the same protein impact has been reported in association with Marfan syndrome and aortic dissection (Proost D et al. Hum. Mutat., 2015 Aug;36:808-14; Fang M et al. Sci Rep, 2017 08;7:10035; Mannucci L et al. Clin. Chim. Acta, 2020 Feb;501:154-164). 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.
GeneDx RCV003128595 SCV003805639 pathogenic not provided 2022-08-02 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; 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
Invitae RCV003765345 SCV004588128 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-07-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr2716*) 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 individual(s) with Marfan syndrome (PMID: 31730815). ClinVar contains an entry for this variant (Variation ID: 222615). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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