Submissions for variant NM_139057.4(ADAMTS17):c.3044C>T (p.Ser1015Leu)

gnomAD frequency: 0.00100  dbSNP: rs143891379

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027768	SCV001190372	uncertain significance	Weill-Marchesani 4 syndrome, recessive	2021-03-30	criteria provided, single submitter	clinical testing	ADAMTS17 NM_139057.3 exon 21 p.Ser1015Leu (c.3044C>T): This variant has not been reported in the literature but is present in 0.01% (119/75650) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-100516333-G-A?dataset=gnomad_r2_1). This variant amino acid Leucine (Leu) is present in >15 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Laboratory Services, Illumina	RCV001027768	SCV001273668	likely benign	Weill-Marchesani 4 syndrome, recessive	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.
Invitae	RCV001572916	SCV002289494	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1015 of the ADAMTS17 protein (p.Ser1015Leu). This variant is present in population databases (rs143891379, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ADAMTS17-related conditions. ClinVar contains an entry for this variant (Variation ID: 827967). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Revvity Omics, Revvity	RCV001027768	SCV003824968	uncertain significance	Weill-Marchesani 4 syndrome, recessive	2021-11-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001572916	SCV004131001	likely benign	not provided	2022-03-01	criteria provided, single submitter	clinical testing	ADAMTS17: BP4
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001572916	SCV001798011	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001572916	SCV001969637	likely benign	not provided		no assertion criteria provided	clinical testing