ClinVar Miner

Submissions for variant NM_014244.5(ADAMTS2):c.115C>T (p.Leu39Phe) (rs1064796637)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482999 SCV000573543 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing The c.115 C>T (L39F) variant of uncertain significance in the ADAMTS2 gene has not been published as pathogenic or been reported as benign to our knowledge. Data from control individuals was not available to assess whether L39F may be a common benign variant in the general population (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). At the mRNA level, this nucleotide position is conserved across species, and in silico splice prediction programs predict the c.115 C>T variant may result in abnormal gene splicing by creating a strong cryptic splice donor site upstream of canonical splice donor site. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. At the protein level, the c.115 C>T (L39F) variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position that is not conserved across species, and 2/3 in silico algorithms predicts this variant likely does not alter the protein structure/function.
Invitae RCV000814048 SCV000954440 uncertain significance Ehlers-Danlos syndrome, type vii, autosomal recessive 2018-12-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 39 of the ADAMTS2 protein (p.Leu39Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with ADAMTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 423799). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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