ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5743C>T (p.Arg1915Cys) (rs1555395826)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589788 SCV000695568 likely pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2016-03-29 criteria provided, single submitter clinical testing Variant summary: This FBN1 c.5743C>T variant affects a highly conserved nucleotide, resulting in amino acid change from Arg to Cys at codon 1915 in the calcium binding EGF-like #28 domain. Cysteine substitution in such domains is known to disrupt the secondary structure of FBN1 protein and possibly impairing fibrillin interactions. 3/4 in-silico tools predict this variant to be damaging, however no functional studies have been published on this missense mutation. This variant was not found in approximately 121094 control chromosomes from the broad and large populations of ExAC. To our knowledge, the variant has not been reported in peer reviewed publications, but has been cited in one MFS patient in the UMD database and 1 familial case referred for genetic testing at our facility. Another missense variant in the same codon, p.R1915S, has been reported in a MFS patient (PMID: 11700157). In addition, there are multiple missense variants (such as p.N1907H, p.N1907K, p.N1907S, p.T1908I, p.I1909S, p.I1909T, p.G1910V, p.F1912C, p.R1915S, p.C1916S, p.C1916Y, etc; source HGMD) in this region that are found in MFS patients indicating that the region or this codon is functionally important. Taken together, mainly based on the nature of this variant in the EGF-like domain, FBN1 c.5743C>T has currently been classified as Likely Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000663814 SCV000787166 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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