ClinVar Miner

Submissions for variant NM_153818.1(PEX10):c.874_875del (p.Leu292fs) (rs61752093)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411962 SCV000487551 pathogenic Peroxisome biogenesis disorder 6A 2016-08-16 criteria provided, single submitter clinical testing
Counsyl RCV000409050 SCV000487552 pathogenic Peroxisome biogenesis disorder 6B 2016-08-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727676 SCV000854989 pathogenic not provided 2017-10-09 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000411962 SCV000355604 pathogenic Peroxisome biogenesis disorder 6A 2017-04-27 criteria provided, single submitter clinical testing The PEX10 c.874_875delCT (p.Leu292ValfsTer66) variant causes a frameshift and is predicted to result in an elongation of the protein. The p.Leu292ValfsTer66 variant has been reported in at least four studies in which it is found in a homozygous state in at least 13 individuals with Zellweger syndrome and in an additional three alleles of unknown zygosity (Okumoto et al. 1998; Shimozawa et al. 2003; Krause et al. 2009; Ebberink et al. 2011). Eleven homozygotes for the p.Leu292ValfsTer66 variant shared a common haplotype, suggesting a founder effect for this variant in the Japanese population (Shimozawa et al. 2003). Control data are unavailable for the variant which is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. The frameshift caused by the p.Leu292ValfsTer66 variant interrupts a RING motif that is essential for protein function (Okumoto et al. 1998). In vivo complementation analyses in patient fibroblasts demonstrated that the p.Leu292ValfsTer66 variant results in a deficiency in PEX10 protein activity (Okumoto et al. 1998). Based on the potential impact of frameshift variants and the supporting evidence, the p.Leu292ValfsTer66 variant is classified as pathogenic for Zellweger syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000590803 SCV000699965 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2016-12-30 criteria provided, single submitter clinical testing Variant summary: The PEX10 c.874_875delCT (p.Leu292Valfs) variant causes a frameshift and is predicted to result in an elongation of the protein. Okumoto_1998 reported the variant to result in a protein entirely lacking the RING motif located immediately downstream of the mutated site, and multiple functional studies show lack of PEX10 activity as a result of the variant. This variant was found in 6/118582 control chromosomes at a frequency of 0.0000506, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX10 variant (0.001118). The variant was reported in numerous affected individual, and was reported as a Japanese founder mutation. Taken together, this variant is classified as pathogenic.
Invitae RCV000800883 SCV000940625 pathogenic Peroxisome biogenesis disorder, complementation group 7 2018-09-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PEX10 gene (p.Leu292Valfs*66). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acids of the PEX10 protein. This variant is present in population databases (rs61752093, ExAC 0.02%). This variant has been observed in several individuals affected with Zellweger peroxisome deficiency syndrome (PMID: 9700193, 12794690, 10862081, 17041890, 19142205, 21031596). This variant has been described as a founder mutation in the Japanese population (PMID: 12794690). It is also known as c.814–815delCT and Leu272fs in the literature. ClinVar contains an entry for this variant (Variation ID: 296273). Experimental studies have shown that this variant disrupts normal PEX10 protein function (PMID: 10862081, 9700193). For these reasons, this variant has been classified as Pathogenic.

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