ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.5626T>C (p.Cys1876Arg)

dbSNP: rs1555395980
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000623517 SCV000740513 pathogenic not provided 2017-07-03 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000659555 SCV000781387 likely pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000623517 SCV000927144 likely pathogenic not provided 2017-02-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV002343175 SCV002651536 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2022-11-17 criteria provided, single submitter clinical testing The p.C1876R variant (also known as c.5626T>C) is located in coding exon 45 of the FBN1 gene. This alteration results from a T to C substitution at nucleotide position 5626. The cysteine at codon 1876 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration is located in the cbEGF-like #27 domain. A different alteration in the same codon, p.C1876Y, has been reported in a 27-year-old patient with aortic root dilation, dural ectasia, and ocular findings with a positive family history which was presumed to be pathogenic due to the high conservation of the cysteine residue in this cbEGF-like domain (Arbustini E et al. Hum Mutat. 2005;26(5):494). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive EGF/cbEGF domain #27. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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