ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1A>C (p.Met1Leu) (rs730880097)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587707 SCV000695475 likely pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2020-08-10 criteria provided, single submitter clinical testing Variant summary: FBN1 c.1A>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 234430 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1A>C in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, other variants affecting p.Met1 (c.1A>T, c.1A>G, c.2T>A, c.3G>A) have been reported to associate with MFS. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics RCV000617649 SCV000738852 pathogenic Cardiovascular phenotype 2016-11-18 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.1A>C), located in coding exon 1 of the FBN1 gene, results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Mutations in this codon have been reported in patients with Marfan syndrome (Rybczynski M et al. Am. J. Med. Genet. A, 2008 Dec;146A:3157-66; Söylen B et al. Clin. Genet., 2009 Mar;75:265-70). 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.
Center for Medical Genetics Ghent,University of Ghent RCV000663511 SCV000786817 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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