Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000029757 | SCV000052410 | uncertain | Marfan syndrome | 2011-08-18 | criteria provided, single submitter | curation | Converted during submission to Uncertain significance. |
| Centre of Medical Genetics, |
RCV000029757 | SCV002025359 | likely pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PS1, PP4 |
| Victorian Clinical Genetics Services, |
RCV000029757 | SCV002769202 | likely 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 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. Null variants with loss of function effects are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects 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 (GeneReviews). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 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) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0702 - Another splice site variant comparable to the one identified in this case has strong previous evidence for pathogenicity. c.5788+5G>A has multiple entries in the FBN1 Universal Mutation Database (UMD), with the majority of patients listed as having classic Marfan syndrome and is consistently classified as pathogenic in ClinVar. Additionally, RT-PCR analysis of cultured fibroblasts from a proband revealed that this variant causes in-frame skipping of exon 47 and a small amount of abnormally spliced transcripts utilized a cryptic splice donor or a cryptic splice acceptor (PMID: 7611299). (SP) 0804 - This variant has previously been described as a variant of uncertain significance in multiple independent cases with consistent phenotype despite being absent in the general population. It has been identified at least two individuals with Marfan Syndrome (PMID: 18435798, 33394117) and classified as a VUS by diagnostic laboratories in ClinVar. (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Center for Medical Genetics Ghent, |
RCV000029757 | SCV000787174 | uncertain significance | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |