Submissions for variant NM_005529.7(HSPG2):c.6071T>A (p.Leu2024His)

gnomAD frequency: 0.00014  dbSNP: rs145943896

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001101114	SCV001257686	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.
Illumina Laboratory Services, Illumina	RCV001101115	SCV001257687	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.
Revvity Omics, Revvity	RCV003132230	SCV003809275	uncertain significance	not provided	2019-11-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003259093	SCV003969376	uncertain significance	Inborn genetic diseases	2023-03-22	criteria provided, single submitter	clinical testing	The c.6071T>A (p.L2024H) alteration is located in exon 47 (coding exon 47) of the HSPG2 gene. This alteration results from a T to A substitution at nucleotide position 6071, causing the leucine (L) at amino acid position 2024 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV003132230	SCV005080370	uncertain significance	not provided	2024-05-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV003132230	SCV005820150	uncertain significance	not provided	2024-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 2024 of the HSPG2 protein (p.Leu2024His). This variant is present in population databases (rs145943896, gnomAD 0.02%). 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: 876383). 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.