Submissions for variant NM_014244.5(ADAMTS2):c.3154T>G (p.Ser1052Ala)

gnomAD frequency: 0.00021  dbSNP: rs201390756

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000842953	SCV000984985	likely benign	not provided	2020-09-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001156652	SCV001318165	uncertain significance	Ehlers-Danlos syndrome, dermatosparaxis type	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001156652	SCV001419681	uncertain significance	Ehlers-Danlos syndrome, dermatosparaxis type	2022-07-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1052 of the ADAMTS2 protein (p.Ser1052Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 682809). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine 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.
Baylor Genetics	RCV001156652	SCV001523970	uncertain significance	Ehlers-Danlos syndrome, dermatosparaxis type	2019-06-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002538338	SCV003560654	uncertain significance	Inborn genetic diseases	2021-10-12	criteria provided, single submitter	clinical testing	The c.3154T>G (p.S1052A) alteration is located in exon 21 (coding exon 21) of the ADAMTS2 gene. This alteration results from a T to G substitution at nucleotide position 3154, causing the serine (S) at amino acid position 1052 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000842953	SCV001550810	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ADAMTS2 p.Ser1052Ala variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs201390756) and ClinVar (classified as likely benign by GeneDx). The variant was identified in control databases in 69 of 269756 chromosomes at a frequency of 0.0002558 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 41 of 9962 chromosomes (freq: 0.004116), Other in 3 of 6756 chromosomes (freq: 0.000444), European (non-Finnish) in 21 of 125002 chromosomes (freq: 0.000168), Latino in 3 of 32450 chromosomes (freq: 0.000092) and African in 1 of 24174 chromosomes (freq: 0.000041), but was not observed in the East Asian, European (Finnish), or South Asian populations. The p.Ser1052 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.