Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001212521 | SCV001384107 | pathogenic | Peroxisome biogenesis disorder | 2019-10-25 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Glu666*) in the PEX6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PEX6-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in PEX6 are known to be pathogenic (PMID: 8670792, 19877282, 21031596). For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV004789478 | SCV005398585 | pathogenic | Peroxisome biogenesis disorder 4A (Zellweger) | 2023-07-17 | 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 peroxisome biogenesis disorder 4A (Zellweger syndrome). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant disease is caused by a single recurring missense p.(Arg860Trp) (OMIM, PMID: 29220678). (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) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic in individuals with Zellweger Syndrome (ClinVar, DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been classified once as pathogenic by one clinical diagnostic laboratory (ClinVar). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000287.3(PEX6):c.1054C>T; p.Gln352*) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (VCGS #20G001271, Invitae). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |