Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002415683 | SCV002717797 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2018-12-06 | criteria provided, single submitter | clinical testing | The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the FBN1 gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This alteration has been previously identified in a patient reported to have Marfan syndrome (MFS) (Groth KA et al. Genet. Med., 2017 07;19:772-777). Multiple mutations in this codon (c.1A>T, c.2T>A, c.3G>A) have been reported in patients with clinical manifestations of MFS (Rybczynski M et al. Am. J. Med. Genet. A, 2008 Dec;146A:3157-66; Tan L et al. Hum. Mol. Genet., 2017 12;26:4814-4822; Takeda N et al. Circ Genom Precis Med, 2018 Jun;11:e002058). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV002516355 | SCV003472781 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-08-13 | criteria provided, single submitter | clinical testing | This sequence change affects the initiator methionine of the FBN1 mRNA. The next in-frame methionine is located at codon 99. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 180349). Disruption of the initiator codon has been observed in individuals with Marfan syndrome (PMID: 27906200; Invitae). |
| Gene |
RCV004589649 | SCV005079176 | pathogenic | not provided | 2023-11-28 | 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); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27906200) |
| Blueprint Genetics | RCV000157222 | SCV000206946 | likely pathogenic | Marfan syndrome | 2014-11-10 | no assertion criteria provided | clinical testing | |
| Center for Medical Genetics Ghent, |
RCV000157222 | SCV000786818 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |