ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.3370T>C (p.Cys1124Arg)

dbSNP: rs2141293730
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002244264 SCV002512685 uncertain significance Marfan syndrome 2021-06-08 criteria provided, single submitter clinical testing ACMG classification criteria: PM2, PP3
GeneDx RCV004779269 SCV005390995 pathogenic not provided 2024-05-01 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12938084)
Ambry Genetics RCV004823019 SCV005585858 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2024-11-29 criteria provided, single submitter clinical testing The p.C1124R variant (also known as c.3370T>C), located in coding exon 27 of the FBN1 gene, results from a T to C substitution at nucleotide position 3370. The cysteine at codon 1124 is replaced by arginine, an amino acid with highly dissimilar properties. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the cbEGF13 domain (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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