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

gnomAD frequency: 0.00707  dbSNP: rs565885690

Total submissions: 8

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529279	SCV000647138	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2025-02-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000413166	SCV000861418	benign	not specified	2018-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000413166	SCV000916425	benign	not specified	2022-11-14	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 0.0071 in 142800 control chromosomes, predominantly at a frequency of 0.011 within the non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within non-Finnish European control individuals in the gnomAD database is approximately 4-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 a benign polymorphism. 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. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=1), likely benign (n=1) / benign (n=4). Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, 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.
CeGaT Center for Human Genetics Tuebingen	RCV002263666	SCV002545381	benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	ADAMTS2: BS1, BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278642	SCV002565923	benign	Ehlers-Danlos syndrome	2022-07-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002523921	SCV003676537	uncertain significance	Inborn genetic diseases	2021-08-02	criteria provided, single submitter	clinical testing	The c.68T>C (p.L23P) alteration is located in exon 1 (coding exon 1) of the ADAMTS2 gene. This alteration results from a T to C substitution at nucleotide position 68, causing the leucine (L) at amino acid position 23 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.