Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000703422 | SCV000832320 | uncertain significance | Exostoses, multiple, type 2 | 2024-09-06 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg465*) in the EXT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXT2 are known to be pathogenic (PMID: 10679937, 19810120). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with EXT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 580003). 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. |
| Fulgent Genetics, |
RCV000762844 | SCV000893203 | pathogenic | Exostoses, multiple, type 2; Seizures-scoliosis-macrocephaly syndrome | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
RCV000703422 | SCV000914285 | uncertain significance | Exostoses, multiple, type 2 | 2019-04-05 | criteria provided, single submitter | clinical testing | The EXT2 c.1393C>T (p.Arg465Ter) variant variant is a stop-gained variant, which was observed 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 for this variant, it 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. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for hereditary multiple osteochondromatosis. |
| Genomic Research Center, |
RCV001169930 | SCV001251660 | pathogenic | not provided | 2020-05-03 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000703422 | SCV004192803 | uncertain significance | Exostoses, multiple, type 2 | 2023-09-06 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV001169930 | SCV004238181 | likely pathogenic | not provided | 2023-11-20 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV000703422 | SCV005399098 | pathogenic | Exostoses, multiple, type 2 | 2022-03-31 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant exostoses, multiple, type 2 (MIM#133701) and autosomal recessive seizures, scoliosis, and macrocephaly syndrome (MIM#616682). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31096510). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 4 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been identified in at least three individuals and classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |