ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.8311G>A (p.Val2771Ile) (rs193922244)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029792 SCV000052446 uncertain significance not specified 2019-01-28 criteria provided, single submitter clinical testing Variant summary: FBN1 c.8311G>A (p.Val2771Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 246138 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in FBN1 causing Marfan Syndrome (5.7e-05 vs 0.00011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.8311G>A in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV000252734 SCV000319240 uncertain significance Cardiovascular phenotype 2014-02-10 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence;In silico models in agreement (benign)
GeneDx RCV000427863 SCV000536361 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN1 gene. The V2771I variant has not been published as pathogenic or been reported as benign to our knowledge. The V2771I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to valine are tolerated across species and where isoleucine is the wild type in multiple species. In silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, the V2771I variant does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Nevertheless, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; Exome Variant Server).
Color RCV000777720 SCV000913665 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-08-27 criteria provided, single submitter clinical testing

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