ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.994C>T (p.Arg332Cys)

gnomAD frequency: 0.00001  dbSNP: rs1161109360
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Vascular Biology, Beijing Anzhen Hospital RCV001374820 SCV001439569 uncertain significance Isolated thoracic aortic aneurysm 2018-09-01 criteria provided, single submitter research
Mayo Clinic Laboratories, Mayo Clinic RCV001508393 SCV001714518 likely pathogenic not provided 2024-01-19 criteria provided, single submitter clinical testing PP2, PP3, PM1, PM2, PS4_moderate
Labcorp Genetics (formerly Invitae), Labcorp RCV001880028 SCV002283851 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-11-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 332 of the FBN1 protein (p.Arg332Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 28973303, 33824467; internal data). ClinVar contains an entry for this variant (Variation ID: 982352). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002379965 SCV002694384 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-02-10 criteria provided, single submitter clinical testing The p.R332C variant (also known as c.994C>T), located in coding exon 9 of the FBN1 gene, results from a C to T substitution at nucleotide position 994. The arginine at codon 332 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the TGFBP #01 domain. 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). This variant has been reported in an individual with sporadic, non-syndromic subclavian aortic dissection (Tan L et al. Hum Mol Genet, 2017 12;26:4814-4822). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen RCV001508393 SCV004702264 uncertain significance not provided 2024-02-01 criteria provided, single submitter clinical testing FBN1: PM2, PS4:Moderate
All of Us Research Program, National Institutes of Health RCV004004932 SCV004823092 uncertain significance Marfan syndrome 2023-05-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 332 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with non-syndromic aortic dissection (PMID: 28973303) and in another individual affected with isolated thoracic aortic aneurysm and dissection (PMID: 33824467). This variant has been identified in 1/251234 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics RCV004004932 SCV005049304 likely pathogenic Marfan syndrome 2024-01-24 criteria provided, single submitter clinical testing
Baylor Genetics RCV004557496 SCV005049491 likely pathogenic Stiff skin syndrome 2024-01-24 criteria provided, single submitter clinical testing

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