ClinVar Genomic variation as it relates to human health

Variant summary: FBN1 c.1090C>T (p.Arg364X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251536 control chromosomes(gnomAD). c.1090C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (e.g. Collod-Beroud_2003, Weerakkody_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.R364* pathogenic mutation (also known as c.1090C>T), located in coding exon 9 of the FBN1 gene, results from a C to T substitution at nucleotide position 1090. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been previously described in multiple patients reported to have classic Marfan syndrome (Rand-Hendriksen S et al. Am J Med Genet. 2007;143A(17):1968-77; Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have rarely been reported (PMID: 27274304; 31950671). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The FBN1 c.1090C>T; p.Arg364Ter variant (rs794728165) is reported in the literature in multiple individuals affected with suspected Marfan syndrome (Baudhuin 2015, Collod-Beroud 2003, Comeglio 2007, Stheneur 2009, Tan 2017, Tjeldhorn 2006, Weerakkody 2018). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 199963), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Baudhuin L et al. Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants. J Hum Genet. 2015 60(5):241-52. Collod-Beroud G et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 2003 22(3):199-208. Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 28(9):928. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 17(9):1121-8 Tan L et al. FBN1 mutations largely contribute to sporadic non-syndromic aortic dissection. Hum Mol Genet. 2017 Dec 15;26(24):4814-4822. Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006 10(4):258-64. 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.

PVS1, PS4_moderate, PM2, PP1

The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant is shared with similarly affected mother (3billion dataset). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000199963 / PMID: 12938084). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change creates a premature translational stop signal (p.Arg364*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 12938084, 17657824, 17663468, 25652356). ClinVar contains an entry for this variant (Variation ID: 199963). For these reasons, this variant has been classified as Pathogenic.

The p.Arg364X variant in FBN1 has been reported in at least 7 individuals with features of Marfan syndrome and segregated with disease in 2 affected individuals from 1 family (Collod-Béroud 2003, Comeglio 2007, Rand-Hendriksen 2007, Stheneur 2009, Baudhuin 2015, Tan 2017, Weerakkody 2018). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 199963). This nonsense variant leads to a premature termination codon at position 364, which is predicted to lead to a truncated or absent protein. Loss of function of the FBN1 gene is an established disease mechanism in autosomal dominant Marfan syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PVS1, PS4, PM2.

Reported numerous times in association with Marfan syndrome and/or TAAD (PMID: 25652356, 12938084, 17253931, 17657824, 17663468, 19293843, 30341550, 29543232); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17253931, 29543232, 34498425, 33648514, 31825148, 25525159, 17657824, 17663468, 19293843, 12938084, 25652356, 28973303, 30341550, 31211624, 33483584, 33824467, 32679894, 33059708, 27535533, 33910934, 35741789, 38094723, 37116669)