Submissions for variant NM_005529.7(HSPG2):c.11200G>A (p.Glu3734Lys)

gnomAD frequency: 0.00010  dbSNP: rs757541406

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001040146	SCV001203707	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3734 of the HSPG2 protein (p.Glu3734Lys). This variant is present in population databases (rs757541406, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with HSPG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 838571). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Illumina Laboratory Services, Illumina	RCV001099732	SCV001256210	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	RCV001099733	SCV001256211	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.
Genomic Medicine Lab, University of California San Francisco	RCV001099732	SCV001573044	uncertain significance	Schwartz-Jampel syndrome	2019-12-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001040146	SCV003811916	uncertain significance	not provided	2019-02-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004031130	SCV004883675	uncertain significance	Inborn genetic diseases	2021-07-06	criteria provided, single submitter	clinical testing	The c.11200G>A (p.E3734K) alteration is located in exon 80 (coding exon 80) of the HSPG2 gene. This alteration results from a G to A substitution at nucleotide position 11200, causing the glutamic acid (E) at amino acid position 3734 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect, ClinGen	RCV001824916	SCV002075207	not provided	Lethal Kniest-like syndrome; Schwartz-Jampel syndrome type 1		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-21-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.