ClinVar Miner

Submissions for variant NM_153818.1(PEX10):c.764dup (p.Leu256fs) (rs61750435)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000007176 SCV000487553 pathogenic Peroxisome biogenesis disorder 6A 2016-07-22 criteria provided, single submitter clinical testing
Counsyl RCV000149808 SCV000487554 pathogenic Peroxisome biogenesis disorder 6B 2016-07-22 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000324305 SCV000858406 pathogenic not provided 2017-11-29 criteria provided, single submitter clinical testing
GeneDx RCV000324305 SCV000329456 pathogenic not provided 2015-12-08 criteria provided, single submitter clinical testing The c.764dupA pathogenic variant in the PEX10 gene has been reported previously, also using alternate nomenclature c.704insA, in association with PEX10-related disorders, in individuals who were heterozygous for the c.746dupA and another variant (Warren et al., 2000; Régal et al., 2010; Ebberink et al., 2011). The c.764dupA variant causes a frameshift starting with codon Leucine 256, changes this amino acid to a Alanine residue, and creates a premature Stop codon at position 103 of the new reading frame, denoted p.Leu256AlafsX103. This variant is not predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies show the c.764dupA variant had 50% of normal PEX10 activity (Warren et al., 2000). The c.764dupA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.764dupA as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000781707 SCV000919970 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2017-09-14 criteria provided, single submitter clinical testing Variant summary: The PEX10 c.764dupA (p.Leu256AlafsX92+) variant causes a frameshift and is predicted to result in an elongation of the protein. One frameshift/elongation variant in PEX10 has been classified as pathogenic by our laboratory (e.g. c.874_875delCT, p.Leu292fsX55+). One in silico tool predicts a damaging outcome for this variant. One functional study showed less than 50% relative rescue activity compared to the wild type (Warren_2000). The variant was found in the control population dataset of ExAC in 2/93566 control chromosomes at a frequency of 0.0000214, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX10 variant (0.001118). This variant was reported in multiple Zellweger syndrome patients, in homozygotes and heterozygotes, including one case of uniparental disomy (Ebberink_2010, Turner_PEX10). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000644606 SCV000766306 pathogenic Peroxisome biogenesis disorder, complementation group 7 2018-12-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PEX10 gene (p.Leu256Alafs*103). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acids of the PEX10 protein. This variant is present in population databases (rs61750435, ExAC 0.004%). This variant has been reported as homozygous or in combination with another PEX10 variant in several individuals affected with Zellweger syndrome spectrum (PMID: 10862081, 19105186, 20695019, 21031596, 17702006). This variant is also known as c.704dupA, c.764_765insA or p.L256fsX102 in the literature. ClinVar contains an entry for this variant (Variation ID: 6774). Experimental studies have shown that this frameshift change causes as reduction in enzyme activity and alters peroxisomal import of catalase in fibroblasts from individuals with this variant (PMID: 10862081, 20695019). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007176 SCV000027372 pathogenic Peroxisome biogenesis disorder 6A 2010-08-01 no assertion criteria provided literature only
OMIM RCV000149808 SCV000196632 pathogenic Peroxisome biogenesis disorder 6B 2010-08-01 no assertion criteria provided literature only

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