Submissions for variant NM_005529.7(HSPG2):c.12982G>A (p.Ala4328Thr)

gnomAD frequency: 0.00254  dbSNP: rs114015043

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000324004	SCV000334681	likely benign	not specified	2015-09-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000316848	SCV000354579	likely benign	Schwartz-Jampel syndrome	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.
Illumina Laboratory Services, Illumina	RCV000378478	SCV000354580	likely benign	Lethal Kniest-like syndrome	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.
Athena Diagnostics Inc	RCV000324004	SCV000613703	benign	not specified	2017-04-10	criteria provided, single submitter	clinical testing
Invitae	RCV000887651	SCV001031222	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000887651	SCV002506018	likely benign	not provided	2023-08-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278272	SCV002566737	likely benign	Connective tissue disorder	2021-05-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000887651	SCV004123413	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	HSPG2: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV003930069	SCV004746628	likely benign	HSPG2-related condition	2022-08-23	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000887651	SCV001549085	likely benign	not provided		no assertion criteria provided	clinical testing	The HSPG2 p.Ala4329Thr variant was not identified in the literature but was identified in dbSNP (ID: rs114015043), LOVD 3.0 and ClinVar (classified as uncertain significance by Illumina, as likely benign by EGL Genetic Diagnostics and Invitae, and as benign by Athena Diagnostics). The variant was identified in control databases in 653 of 282252 chromosomes (1 homozygous) at a frequency of 0.002314 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 551 of 128660 chromosomes (freq: 0.004283), Other in 17 of 7216 chromosomes (freq: 0.002356), Latino in 59 of 35424 chromosomes (freq: 0.001666), African in 14 of 24922 chromosomes (freq: 0.000562), South Asian in 8 of 30616 chromosomes (freq: 0.000261), European (Finnish) in 3 of 25104 chromosomes (freq: 0.00012) and Ashkenazi Jewish in 1 of 10362 chromosomes (freq: 0.000097), but was not observed in the East Asian population. The p.Ala4329 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000887651	SCV001798899	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000887651	SCV001930398	likely benign	not provided		no assertion criteria provided	clinical testing