ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.2645C>T (rs794728195)

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Total submissions: 12
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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 2020-08-27 criteria provided, single submitter clinical testing The p.A882V pathogenic mutation (also known as c.2645C>T), located in coding exon 21 of the FBN1 gene, results from a C to T substitution at nucleotide position 2645. The alanine at codon 882 is replaced by valine, an amino acid with similar properties, and is located in the hybrid motif #02 domain. This mutation has been reported in several individuals with Marfan syndrome (Loeys B et al. Hum. Mutat. 2004;24:140-6; Comeglio P et al. Hum. Mutat. 2007;28:928), and was indicated to have occurred de novo​ in an individual with Marfan syndrome; however, there was no information provided regarding his clinical diagnosis, family history, or parental testing (Spits C et al. Fertil. Steril. 2006;86:310-20). This mutation was also identified in an individual with ectopia lentis, minor skeletal and skin involvement, and no cardiovascular findings (Comeglio P et al. Hum. Mutat. 2007;28:928) and has been detected in aortic aneurysm and dissection cohorts (Weerakkody R et al. Genet. Med. 2018;20(11):1414-1422; Overwater E et al. Hum. Mutat. 2018;39(9):1173-1192). This mutation co-segregated with disease in one family tested in our laboratory and was reported to segregate with disease in at least two additional families (Comeglio P et al. Hum. Mutat., 2007 Sep;28:928; Howarth R et al. Genet. Test., 2007;11:146-52). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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; Familial thoracic aortic aneurysm and aortic dissection 2020-10-06 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001395 SCV001158601 likely pathogenic not specified 2019-05-06 criteria provided, single submitter clinical testing The FBN1 c.2645C>T; p.Ala882Val variant (rs794728195) has been described in several individuals with Marfan syndrome or other FBN1-related disorders (Comeglio 2007, Howarth 2007, Loeys 2004, Weerakkody 2018). It is reported as pathogenic/likely pathogenic by multiple sources in ClinVar (Variation ID: 200001) and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at codon 882 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered likely pathogenic. REFERENCES Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. Howarth R et al. Application of dHPLC for mutation detection of the fibrillin-1 gene for the diagnosis of Marfan syndrome in a National Health Service Laboratory. Genet Test. 2007 Summer;11(2):146-52. Loeys B et al. Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum Mutat. 2004 Aug;24(2):140-6. Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000616479 SCV001333961 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2019-02-22 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198804 SCV001369799 likely pathogenic Marfan lipodystrophy syndrome 2018-10-24 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000663562 SCV001433236 likely pathogenic Marfan syndrome 2020-02-10 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000181465 SCV001449807 pathogenic not provided 2015-04-07 criteria provided, single submitter clinical testing
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000616479 SCV000731212 likely pathogenic Familial 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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