Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001184857 | SCV001350943 | likely benign | Familial thoracic aortic aneurysm and aortic dissection | 2023-08-10 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001255475 | SCV001431892 | likely benign | not specified | 2020-08-10 | criteria provided, single submitter | clinical testing | Variant summary: FBN1 c.1277C>T (p.Pro426Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 282654 control chromosomes, predominantly at a frequency of 0.0005 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1277C>T has been reported in the literature as an incidental finding, in a Korean individual in a whole exome sequencing study (Kwak_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |
| ARUP Laboratories, |
RCV001811687 | SCV001477793 | uncertain significance | not provided | 2020-04-04 | criteria provided, single submitter | clinical testing | The FBN1 c.1277C>T; p.Pro426Leu variant (rs146044644), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is only observed on ten alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 426 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Pro426Leu variant is uncertain at this time. |
| Labcorp Genetics |
RCV002067950 | SCV002477261 | likely benign | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-10-13 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004803505 | SCV005424919 | uncertain significance | Marfan syndrome | 2024-03-05 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with leucine at codon 426 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 12/282654 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |