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
Labcorp Genetics (formerly Invitae), Labcorp RCV003765345 SCV004588128 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-07-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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.

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