Submissions for variant NM_005529.7(HSPG2):c.12874G>A (p.Glu4292Lys)

gnomAD frequency: 0.00135  dbSNP: rs141280063

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000711912	SCV000233243	uncertain significance	not provided	2014-06-23	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV004998388	SCV000842323	likely benign	not specified	2024-08-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711912	SCV001057025	benign	not provided	2025-01-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001101422	SCV001258027	benign	Lethal Kniest-like syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001101423	SCV001258028	benign	Schwartz-Jampel syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000711912	SCV001472330	uncertain significance	not provided	2019-08-02	criteria provided, single submitter	clinical testing	The HSPG2 c.12874G>A; p.Glu4292Lys variant (rs141280063) is reported in the literature in an individual with idiopathic scoliosis (Baschal 2014), though, to our knowledge, it has not been described in association with a congenital skeletal dysplasia. This variant is found in the Finnish European population with an overall allele frequency of 0.98% (243/24858 alleles) in the Genome Aggregation Database. The glutamate at codon 4292 is weakly conserved and computational analyses (SIFT: tolerate, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Glu4292Lys variant is uncertain at this time. References: Baschal EE et al. Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis. G3 (Bethesda). 2014 Dec 12;5(2):167-74
GeneDx	RCV000711912	SCV001793163	likely benign	not provided	2019-12-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30753492, 25504735)
PreventionGenetics, part of Exact Sciences	RCV004539697	SCV004760228	benign	HSPG2-related disorder	2019-10-31	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).