ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.5303T>C (p.Val1768Ala) (rs779202876)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000195602 SCV000250221 uncertain significance not provided 2015-05-08 criteria provided, single submitter clinical testing p.Val1768Ala (V1768A) GTG>GCG: c.5303 T>C in exon 41 of the FBN2 gene (NM_001999.3) The V1768A variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V1768A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V1768A 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-PANCARD
Invitae RCV000233352 SCV000287267 uncertain significance Congenital contractural arachnodactyly 2016-03-15 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1768 of the FBN2 protein (p.Val1768Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs779202876, ExAC 0.008%) but has not been reported in the literature in individuals with a FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 213338). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000233352 SCV000781464 uncertain significance Congenital contractural arachnodactyly 2016-11-01 criteria provided, single submitter clinical testing

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