ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.4724G>A (p.Arg1575His) (rs776040052)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000518903 SCV000618111 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The R1575H variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 5/126,236 alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, R1575H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthrmore, the R1575H variant does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with CCA (Collod-Beroud et al., 2003; Frederic et al., 2009).
Ambry Genetics RCV000618583 SCV000739030 uncertain significance Cardiovascular phenotype 2017-06-07 criteria provided, single submitter clinical testing The p.R1575H variant (also known as c.4724G>A), located in coding exon 37 of the FBN2 gene, results from a G to A substitution at nucleotide position 4724. The arginine at codon 1575 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001306832 SCV001496214 uncertain significance Congenital contractural arachnodactyly 2020-08-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1575 of the FBN2 protein (p.Arg1575His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs776040052, ExAC 0.03%). This variant has not been reported in the literature in individuals with FBN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 449742). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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