Variant summary: FBN1 c.6658C>T (p.Arg2220X) 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. The variant was absent in 250986 control chromosomes (gnomAD). c.6658C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (Attanasio_2013, Becerra-Munoz_2018, Comeglio_2007, Franken_2016, Matsukawa_2001). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: 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 has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042407 / PMID: 11139245 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Identified in a patient with isolated TAAD (iTAAD) in published literature (PMID: 33824467); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 39843441, 34916231, 36517271, 25525159, 21907952, 17657824, 12938084, 23684891, 22772377, 27112580, 29357934, 26787436, 35058154, 33824467, 11139245)

The Arg2220X variant (FBN1) has been reported in two Japanese probands with clin ical features of Marfan syndrome and was absent in 100 control chromosomes from healthy Japanese individuals (Matsukawa 2001, Ogawa 2011). In addition, this var iant has been identified in 1/1090 chromosomes from a broad, though clinically a nd racially unspecified population (dbSNP rs113001196). This nonsense variant le ads to a premature termination codon at position 2220, which is predicted to lea d to a truncated or absent protein. Loss of function in the FBN1 gene is an est ablished disease mechanism in Marfan patients. In summary, this variant is likel y to be pathogenic, though segregation studies and functional analyses are requi red to fully establish the pathogenicity of this variant. The clinical significa nce of this sequence variant should be interpreted in the context of this indivi dual's clinical manifestation.

The FBN1 c.6658C>T; p.Arg2220Ter variant (rs113001196) has been described in several individuals affected with Marfan syndrome (Attanasio 2013, Collod-Beroud 2003, Comeglio 2007, Matsukawa 2001, Ogawa 2011, Wang 2013). It is reported as pathogenic in ClinVar (Variation ID: 42407), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and 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 pathogenic. Pathogenic FBN1 variants are most commonly causative for Marfan syndrome (MFS); clinical manifestations are variable. Additionally, other phenotypes including neonatal Marfan syndrome, mitral valve prolapse syndrome, MASS syndrome, thoracic aortic aneurysms and aortic dissections (TAAD), Shprintzen-Goldberg syndrome, Weill-Marchesani syndrome as well as autosomal dominant ectopia lentis are also associated with FBN1 pathogenic variants. Offspring of this individual have a 50 percent chance of inheriting the causative variant. References: Attanasio M et al. Dural ectasia and FBN1 mutation screening of 40 patients with Marfan syndrome and related disorders: role of dural ectasia for the diagnosis. Eur J Med Genet. 2013 Jul;56(7):356-60. Collod-Beroud G et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 2003 Sep;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 Sep;28(9):928. Matsukawa R et al. Eight novel mutations of the FBN1 gene found in Japanese patients with Marfan syndrome. Hum Mutat. 2001;17(1):71-2. Ogawa N et al. Evaluating Japanese patients with the Marfan syndrome using high-throughput microarray-based mutational analysis of fibrillin-1 gene. Am J Cardiol. 2011 Dec 15;108(12):1801-7. Wang WJ et al. Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections. J Mol Med (Berl). 2013 Jan;91(1):37-47.

The p.R2220* pathogenic mutation (also known as c.6658C>T), located in coding exon 54 of the FBN1 gene, results from a C to T substitution at nucleotide position 6658. This changes the amino acid from an arginine to a stop codon within coding exon 54. This alteration has been reported in cohorts of subjects with FBN1-related disease (Matsukawa R et al. Hum Mutat, 2001;17:71-2; Comeglio P et al. Hum Mutat, 2007 Sep;28:928; Somers AE et al. Am J Med Genet A, 2016 Jul;170:1786-90; Becerra-Mu&ntilde;oz VM et al. Orphanet J Rare Dis, 2018 Jan;13:16; Meester JAN et al. Genet Med, 2022 May;24:1045-1053). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

A heterozygous nonsense variant was identified, NM_000138.4(FBN1):c.6658C>T in exon 55 of 66 of the FBN1 gene. This nonsense variant is predicted to create a change of arginine to a stop at amino acid position 2220 of the protein, NP_000129.3(FBN1):p.(Arg2220*), resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is not present in the gnomAD population database. It has been previously reported in patients with Marfan syndrome (ClinVar; Becerra-Munoz, V.M. et al., 2018). Other variants predicted to cause NMD have been reported as pathogenic in individuals with this condition (ClinVar). Subsequent analysis of parental samples indicated this variant to be de novo. Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

PM2, PVS1, PP4

This sequence change creates a premature translational stop signal (p.Arg2220*) 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 individual(s) with Marfan syndrome (PMID: 11139245, 17657824, 22772377, 23684891, 27112580, 29357934). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 42407). For these reasons, this variant has been classified as Pathogenic.