Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000458027 | SCV000544844 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-04-07 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 19293843, 21542060; Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 406283). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2247 of the FBN1 protein (p.Asp2247Gly). |
| Ce |
RCV001093331 | SCV001250258 | pathogenic | not provided | 2019-01-01 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001192807 | SCV001361168 | uncertain significance | not specified | 2019-09-30 | criteria provided, single submitter | clinical testing | Variant summary: FBN1 c.6740A>G (p.Asp2247Gly) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. The variant is located at the first 5' nucleotide position of exon 56, therefore, could affect splicing. Five of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250566 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6740A>G has been reported in the literature in individuals affected with classic Marfan Syndrome (Baetens_2011, Stheneur_2009). However, limited available information is provided (ie, lack of co-occurrence and cosegregation data). These reports do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. In addition, other missense variants effecting the same codon, D2247Y and D2247V, along with nearby codons, C2245G, C2245S, C2245Y, D2249G, have been reported in association with MFS via HGMD. Therefore, suggesting the region may be important for FBN1 protein function. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Centre of Medical Genetics, |
RCV000663896 | SCV002025414 | likely pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PS6, PP4 |
| Center for Medical Genetics Ghent, |
RCV000663896 | SCV000787262 | uncertain significance | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |