ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.217C>A (p.Arg73Ser) (rs148493036)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198722 SCV000250148 uncertain significance not provided 2018-08-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The R73S variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 23/22850 (0.1%) alleles from individuals of African ancestry in large population cohorts, indicating it may be a rare benign variant in this population (Lek et al., 2016). Additionally, the R73S variant does not affect a cysteine residue within a calcium-binding EGFlike domain of the FBN2 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with congenital contractural arachnodactyly (Collod-Beroud et al., 2003; Frédéric et al., 2009). Nevertheless, the R73S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000252340 SCV000319386 uncertain significance Cardiovascular phenotype 2018-07-03 criteria provided, single submitter clinical testing The p.R73S variant (also known as c.217C>A), located in coding exon 1 of the FBN2 gene, results from a C to A substitution at nucleotide position 217. The arginine at codon 73 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is not well 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 variant remains unclear.
Invitae RCV001484140 SCV001688550 likely benign Congenital contractural arachnodactyly 2020-09-19 criteria provided, single submitter clinical testing

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