ClinVar Miner

Submissions for variant NM_014244.5(ADAMTS2):c.68T>C (p.Leu23Pro) (rs565885690)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000413166 SCV000861418 benign not specified 2018-06-06 criteria provided, single submitter clinical testing
GeneDx RCV000413166 SCV000491340 uncertain significance not specified 2016-11-23 criteria provided, single submitter clinical testing The L23P variant in the ADAMTS2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The 1000 Genomes Database reports L23P was observed in 9/1322 0.68%) alleles from individuals of African background and in 3/1006 (0.3%) alleles from individuals of European background. The L23P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret L23P as a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000413166 SCV000916425 likely benign not specified 2018-08-29 criteria provided, single submitter clinical testing Variant summary: ADAMTS2 c.68T>C (p.Leu23Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0063 in 28106 control chromosomes (gnomAD). The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in ADAMTS2 causing Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) phenotype (0.0029), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.68T>C in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000529279 SCV000647138 uncertain significance Ehlers-Danlos syndrome, type vii, autosomal recessive 2018-01-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 23 of the ADAMTS2 protein (p.Leu23Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a ADAMTS2-related disease. ClinVar contains an entry for this variant (Variation ID: 372811). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on ADAMTS2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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