Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV000663502 | SCV005398530 | likely pathogenic | Marfan syndrome | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely 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. Missense with both dominant negative and loss of function effects on protein function, are also associated with causing Marfan syndrome and ectopia lentis (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and compounded by variable expressivity (GeneReviews). (I) 0108 - This gene is associated with both recessive and dominant disease. Patients with a recessive form of disease have Marfan syndrome; however, there are very few reports (OMIM). (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 (GeneReviews, OMIM). (I) 0216 - In-frame insertion/deletion in a non-repetitive region that has uninformative conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated calcium-binding EGF-like (10) domain (UniProt). (I) 0705 - No comparable in-frame deletion variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been identified in a 5 year old classic Marfan syndrome patient (PMID: 11700157, ClinVar) and the variant in this case is reported to be de novo on the Universal Mutation Database – FBN1. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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 |
| Center for Medical Genetics Ghent, |
RCV000663502 | SCV000786802 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |