ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.3839C>T (p.Ser1280Leu) (rs200481467)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000513271 SCV000250286 uncertain significance not provided 2019-01-15 criteria provided, single submitter clinical testing The S1280L variant of uncertain significance in the FBN2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant has been seen in other individuals referred for heritable disorders of connective tissue testing at GeneDx. S1280L has also been observed in 13/126,530 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The S1280L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, although this variant is located within a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a cysteine residue. 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; Frederic et al., 2009).
Invitae RCV000472155 SCV000553192 likely benign Congenital contractural arachnodactyly 2020-09-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513271 SCV000609174 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620430 SCV000739037 uncertain significance Cardiovascular phenotype 2020-05-19 criteria provided, single submitter clinical testing The p.S1280L variant (also known as c.3839C>T), located in coding exon 29 of the FBN2 gene, results from a C to T substitution at nucleotide position 3839. The serine at codon 1280 is replaced by leucine, an amino acid with dissimilar properties, and is located in the cbEGF-like #17 domain. 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 alteration remains unclear.
GenomeConnect, ClinGen RCV000513271 SCV000840353 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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