ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.2480G>A (p.Arg827Gln) (rs150735582)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197430 SCV000250170 uncertain significance not provided 2014-12-29 criteria provided, single submitter clinical testing p.Arg827Gln (CGA>CAA): c.2480 G>A in exon 19 of the FBN2 gene (NM_001999.3) The R827Q variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R827Q variant was not observed with any significant frequency 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 R827Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs in the EGF-like 12 calcium-binding domain at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no missense mutations in nearby residues have been reported in association with CCA, indicating that 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 TAADV2-1,TAAD
Invitae RCV000206321 SCV000262021 uncertain significance Congenital contractural arachnodactyly 2015-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 827 of the FBN2 protein (p.Arg827Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs150735582, ExAC 0.02%) but has not been reported in the literature. 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 C0"). In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000248195 SCV000319331 uncertain significance Cardiovascular phenotype 2014-10-30 criteria provided, single submitter clinical testing The p.R827Q variant (also known as c.2480G>A), located in coding exon 19 of the FBN2 gene<span style="background-color: initial;">in the cb EGF-like #09 domain<span style="background-color: initial;">, results from a G to A substitution at nucleotide position 2480. The arginine at codon 827 is replaced by glutamine, an amino acid with some similar properties. This variant was previously reported in the SNPDatabase as rs150735582. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13,006), having been observed in 0.01% (1/8600) of European American alleles and in none of 4406 African American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging<span style="background-color: initial;">by PolyPhen but<span style="background-color: initial;">tolerated by SIFT <em style="background-color: initial;">in silico<span style="background-color: initial;"> analyses.<span style="background-color: initial;">Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

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