ClinVar Genomic variation as it relates to human health

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.

This missense variant replaces alanine with valine at codon 882 of hybrid motif 2 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 six unrelated individuals affected with Marfan syndrome (PMID: 15241795, 16756980, 17657824, 19839986), in three individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 28973303, 29543232, 29907982), and in another three individuals with Marfan syndrome-related features (PMID: 20564469, 25652356, 17627385). It has been shown that this variant segregates with Marfan syndrome in a family with four affected carriers (communication with an external laboratory, ClinVar SCV000739791.3). This variant has been described as de novo in one of the probands with Marfan syndrome, although parental testing information was not provided (PMID: 16756980). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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.

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.

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.

ACMG criteria used to clasify this variant: PP3, PM1, PS4, PM2, PM5

Described as de novo in one of these probands, although no specific clinical or family history information was provided (Spits et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although 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 (HGMD; Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 21895641, 20564469, 19161152, 17627385, 16756980, 19839986, 17657824, 28973303, 30341550, 29907982, 29543232, 32123317, 12938084, 15241795)

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 882 of the FBN1 protein (p.Ala882Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome or thoracic aortic aneurysm and dissection (PMID: 15241795, 16756980, 19161152, 19839986, 20564469, 28973303). ClinVar contains an entry for this variant (Variation ID: 200001). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.