ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2645C>T (p.Ala882Val) (rs794728195)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181465 SCV000233767 likely pathogenic not provided 2018-05-24 criteria provided, single submitter clinical testing The A882V likely pathogenic variant was identified in the FBN1 gene. This variant has been reported in individuals who meet Ghent criteria for a diagnosis of Marfan syndrome (MFS) and in individuals with ectopia lentis (EL) who do not meet Ghent criteria for MFS (Loeys et al., 2004; Spits et al., 2006; Comeglio et al., 2007; Howarth et al., 2007; Hung et al., 2009; Turner et al., 2009; Aragon-Martin et al., 2010). Loeys et al. (2004) first reported A882V as a novel variant in a 24 year-old patient who fulfilled Ghent criteria for a diagnosis of MFS based on major ocular and cardiovascular system involvement and minor skeletal involvement with no reported family history. Spits et al. (2006) reported A882V as a de novo variant in man with MFS who was pursuing preimplantation genetic diagnosis (PGD) for MFS; however, no specific clinical or family history information was provided. In addition, this variant has been reported in an individual with non-syndromic aortic dissection (Tan et al., 2017). The A882V variant is not observed in large population cohorts (Lek et al., 2016). While the A882V variant results in a conservative amino acid substitution, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Though this variant does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which represents the majority of pathogenic missense changes associated with Marfan syndrome, it is located in the Hybrid 2 domain and several nearby missense variants in this domain (G880S, G880D, G884E) have been reported in association with Marfan syndrome in HGMD and in the UMD-FBN1 database (Stenson et al., 2014; Collod-Beroud et al., 2003). In summary, A882V in the FBN1 gene is interpreted as a likely pathogenic variant.
Ambry Genetics RCV000617207 SCV000739791 pathogenic Cardiovascular phenotype 2017-02-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Other strong data supporting pathogenic classification
Fulgent Genetics,Fulgent Genetics RCV000763356 SCV000894046 pathogenic Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780242 SCV000917350 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2017-10-31 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.2645C>T (p.Ala882Val) variant involves the alteration of a highly conserved nucleotide that resides within one of the TB domains (InterPro). 4/4 in silico tools used predict a damaging outcome for this variant. This variant is absent from control dataset of gnomAD and several control cohorts reported in the literature (~246118 chrs tested), but was identified in multiple affected individuals presenting with classical MFS, isolated EL and incomplete MFS (Loeys_2004; Spits_2006; Comeglio_2006; Howarth_2007; Turner_2009; Hung_2009). The variant appears to segregate with the disease (Howarth_2007). In addition, one clinical lab cites the variant with classification of Likely Pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000807820 SCV000947894 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 882 of the FBN1 protein (p.Ala882Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Marfan syndrome or thoracic aortic aneurysm and dissection (PMID: 15241795, 20564469, 28973303, 19161152, 19839986, 16756980). ClinVar contains an entry for this variant (Variation ID: 200001). 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: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000616479 SCV000731212 likely pathogenic Thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
Center for Medical Genetics Ghent,University of Ghent RCV000663562 SCV000786873 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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