Submissions for variant NM_005529.7(HSPG2):c.9564G>C (p.Gln3188His)

gnomAD frequency: 0.00066  dbSNP: rs149644947

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000367014	SCV000354697	uncertain significance	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, 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	RCV000274765	SCV000354698	uncertain significance	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, 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.
GeneDx	RCV000414737	SCV000491983	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing	The Q3188H variant in the HSPG2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports Q3188H was observed in 11/8600 alleles (0.13%) from individuals of European ancestry, indicating it may be a rare variant in this population. The Q3188H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution also occurs at a position that is conserved across mammalian species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret Q3188H as a variant of uncertain significance.
Athena Diagnostics	RCV000414737	SCV001475897	benign	not specified	2024-10-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001348418	SCV001542721	likely benign	not provided	2024-11-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001348418	SCV002049076	uncertain significance	not provided	2021-09-09	criteria provided, single submitter	clinical testing	The HSPG2 c.9564G>C; p.Gln3188His variant (rs149644947), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 295756). It is observed in the Ashkenazi Jewish population at an overall frequency of 0.43% (45/10370 alleles) in the Genome Aggregation Database. The glutamine at codon 3188 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.353). Due to limited evidence, the clinical significance of the p.Gln3188His variant is uncertain at this time.
Ambry Genetics	RCV002522108	SCV003678421	likely benign	Inborn genetic diseases	2021-11-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV001348418	SCV003811329	uncertain significance	not provided	2021-05-03	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001348418	SCV001798418	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001348418	SCV001966407	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004543166	SCV004785415	likely benign	HSPG2-related disorder	2022-04-01	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).