Submissions for variant NM_000138.5(FBN1):c.5917+5G>A

dbSNP: rs1555395743

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre of Medical Genetics, University of Antwerp	RCV002246043	SCV002025372	uncertain significance	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PM8, PP4
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002246043	SCV005398558	likely pathogenic	Marfan syndrome	2020-10-19	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 (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are also associated with causing Marfan syndrome and additionally, 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) 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) 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 predictions by in silico tools are conflicting but affected nucleotide is highly conserved. (I) 0710 - Another splice variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. A splice variant at the same nucleotide position (c.5917+5G>T) has been reported as a VUS in a patient with Marfan syndrome (ClinVar). (I) 0802 - This variant has moderate previous evidence of pathogenicity in an unrelated individual. This variant has been classified as pathogenic and reported in a patient with Marfan syndrome (PMID: 11826022), and a de novo patient with cardiac defects, ectopia lentis and arachnodactyly (Decipher). (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) (VCGS #18G003425, 18G004342). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign