ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.1277C>T (p.Pro426Leu)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV001184857 SCV001350943 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2018-12-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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, Molecular Genetics and Genomics,ARUP Laboratories RCV001289803 SCV001477793 uncertain significance none 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.

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