Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000797185 | SCV000936731 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2018-07-30 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 56 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. This variant has been observed to segregate with aortic dissection and Marfan syndrome in two families (PMID: 24610719, Invitae). Experimental studies have shown that this intronic missense causes the generation of a pseudo-exon between exons 56 and 57 which results in reduced protein expression (PMID: 24610719). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV002470985 | SCV002768255 | pathogenic | Marfan syndrome | 2022-06-24 | criteria provided, single submitter | clinical testing | 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 been reported infrequently (PMIDs: 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) 0217 - Non-coding variant with known effect. Analysis of cDNA from a patient's cultured fibroblasts showed this intronic variant created a new splice donor site, resulting in the integration of a 90-bp pseudo-exon in between exons 56 and 57 containing a stop codon, causing nonsense-mediated mRNA decay (NMD; PMID: 24610719). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported as heterozygous in a family with Marfan syndrome (PMID: 24610719), and as likely pathogenic once in ClinVar. (SP) 0901 - This variant has strong evidence for segregation with disease. It has been shown to segregate with disease in an extended family with seven affected and four unaffected family members (PMID: 24610719). (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 |