ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Invitae RCV000529279 SCV000647138 benign Ehlers-Danlos syndrome dermatosparaxis type 2019-12-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000413166 SCV000861418 benign not specified 2018-06-06 criteria provided, single submitter clinical testing
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.
Illumina Clinical Services Laboratory,Illumina RCV000529279 SCV001315932 likely benign Ehlers-Danlos syndrome dermatosparaxis type 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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