Submissions for variant NM_000138.5(FBN1):c.1A>C (p.Met1Leu)

dbSNP: rs730880097

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663511	SCV004037324	pathogenic	Marfan syndrome	2023-09-26	reviewed by expert panel	curation	NM_000138.5 c.1A>C alters the methionine at amino acid position 1, which functions as the translation initiation codon, and is considered a start-loss variant. This is expected to result in an absent or disrupted protein product due to loss of protein translation, N-terminal truncation, or alteration of the reading frame (PVS1_moderate). Start-loss variants have been reported in the literature in at least 6 individuals with features suggestive of Marfan syndrome and in 1 individual with a clinical diagnosis of Marfan syndrome (PS4; PMIDs: 19012347, 19159394, 27611364, 29357934, 28973303, 29848614, 35058154). In one of these individuals with a non-specific phenotype and in another with a phenotype consistent with FBN1 but not highly specific, a start-loss variant was found to be de novo with maternity and paternity unconfirmed (PM6; PMIDs: 28973303, 35058154). A start-loss variant was also identified in an internal family of 2 siblings with clinical diagnoses of Marfan syndrome (PP4; Bichat). This specific variant has been reported in ClinVar as pathogenic and likely pathogenic (Variation ID: 495569). This variant and all other start-loss variants are absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PVS1_moderate, PM6, PM2_supporting, PP4.
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	RCV002315883	SCV000738852	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	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