Submissions for variant NM_005529.7(HSPG2):c.4601C>G (p.Pro1534Arg)

gnomAD frequency: 0.00133  dbSNP: rs142736845

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726026	SCV000341316	uncertain significance	not provided	2016-05-03	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000726026	SCV000613725	benign	not provided	2021-07-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765078	SCV000896283	uncertain significance	Lethal Kniest-like syndrome; Schwartz-Jampel syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726026	SCV001095718	likely benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001097664	SCV001253962	uncertain significance	Schwartz-Jampel syndrome	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.
Illumina Laboratory Services, Illumina	RCV001097665	SCV001253963	uncertain significance	Lethal Kniest-like syndrome	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000320580	SCV001370565	uncertain significance	not specified	2024-04-03	criteria provided, single submitter	clinical testing	Variant summary: HSPG2 c.4601C>G (p.Pro1534Arg) results in a non-conservative amino acid change located in the Laminin EGF domain (IPR002049) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 1610498 control chromosomes in the gnomAD database, including 7 homozygotes. To our knowledge, no occurrence of c.4601C>G in individuals affected with HSPG2-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 287524). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneDx	RCV000726026	SCV001816279	likely benign	not provided	2020-12-28	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278305	SCV002566764	uncertain significance	Connective tissue disorder	2021-03-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535386	SCV004755219	likely benign	HSPG2-related disorder	2022-04-12	no assertion criteria provided	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).