Submissions for variant NM_005529.7(HSPG2):c.5648C>T (p.Ala1883Val)

gnomAD frequency: 0.00078  dbSNP: rs140954748

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725443	SCV000336972	uncertain significance	not provided	2017-11-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000372843	SCV000354869	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	RCV000278295	SCV000354870	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.
Athena Diagnostics	RCV000376732	SCV000613734	likely benign	not specified	2024-09-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000376732	SCV000885579	uncertain significance	not specified	2019-06-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765077	SCV000896282	uncertain significance	Lethal Kniest-like syndrome; Schwartz-Jampel syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000725443	SCV001485839	uncertain significance	not provided	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1883 of the HSPG2 protein (p.Ala1883Val). This variant is present in population databases (rs140954748, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 284377). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine 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.
GeneDx	RCV000725443	SCV001821009	likely benign	not provided	2020-08-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725443	SCV003809302	uncertain significance	not provided	2020-07-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535319	SCV004119836	uncertain significance	HSPG2-related disorder	2023-06-23	criteria provided, single submitter	clinical testing	The HSPG2 c.5648C>T variant is predicted to result in the amino acid substitution p.Ala1883Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-22182333-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.