ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6032G>A (p.Cys2011Tyr) (rs886038967)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000242615 SCV000319401 likely pathogenic Cardiovascular phenotype 2015-03-19 criteria provided, single submitter clinical testing The p.C2011Y variant (also known as c.6032G>A), located in coding exon 48 of the FBN1 gene, results from a G to A substitution at nucleotide position 6032. The cysteine at codon 2011 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #30 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). Internal structural analysis indicates that this alteration eliminates a structurally critical disulfide in the structurally sensitive cbEGF domain #30 (Ambry internal data). A likely pathogenic alteration, p.C2011R, has been described in the same codon (Overwater E et al. Hum. Mutat., 2018 Sep;39:1173-1192). 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.
GeneDx RCV000413845 SCV000490525 likely pathogenic not provided 2019-03-28 criteria provided, single submitter clinical testing 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 (Collod-Beroud et al., 2003).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260318 SCV001437243 uncertain significance not specified 2020-09-16 criteria provided, single submitter clinical testing Variant summary: FBN1 c.6032G>A (p.Cys2011Tyr) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251146 control chromosomes (gnomAD). To our knowledge, no occurrence of c.6032G>A in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, missense mutations affecting or creating cysteine residues or located within the conserved resides of the EGF consensus sequence are listed among the criteria for a causal FBN1 mutation when identified as de-novo (with proven paternity) in the revised Ghent criteria for the diagnosis of Marfan and related conditions (Loeys, BL et al, 2010). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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