ClinVar Miner

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

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Total submissions: 4
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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 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.
Invitae RCV001240585 SCV001413547 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-04-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1915 of the FBN1 protein (p.Arg1915Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 27906200, 27234404). ClinVar contains an entry for this variant (Variation ID: 495629). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Medical Genetics Ghent,University of Ghent RCV000663814 SCV000787166 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000663814 SCV001192850 likely pathogenic Marfan syndrome 2017-08-09 no assertion criteria provided clinical testing

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