ClinVar Miner

Submissions for variant NM_002617.4(PEX10):c.2T>C (p.Met1Thr)

dbSNP: rs724160002
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665679 SCV000789838 pathogenic Peroxisome biogenesis disorder 6A (Zellweger); Peroxisome biogenesis disorder 6B 2017-02-24 criteria provided, single submitter clinical testing
Invitae RCV001850029 SCV002232540 pathogenic Peroxisome biogenesis disorder, complementation group 7 2023-10-05 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the PEX10 mRNA. The next in-frame methionine is located at codon 145. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with peroxisomal biogenesis disorders (PMID: 20695019, 28320181). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162434). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155088 SCV003845118 pathogenic Peroxisome biogenesis disorder 2023-02-21 criteria provided, single submitter clinical testing Variant summary: PEX10 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream in-frame methionine is at codon 145 (Exon 3). Other variants impacting the PEX10 start codon have been reported as pathogenic in ClinVar and HGMD (e.g., c.1A>G/p.M1V). Additionally, truncating variants downstream of the start-loss but upstream of the potential new start codon have been classified as pathogenic by our laboratory. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 26612 control chromosomes. c.2T>C has been reported in the literature in individuals affected with peroxisomal biogenesis disorders and ataxia (e.g., Regal_2010, Ebberink_2010) and has been shown to segregate with disease in related individuals (e.g., Yamashita_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that PEX10 was defective in fibroblasts from a compound heterozygous patient (with a null variant in trans; Regal_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000149812 SCV000196636 pathogenic Peroxisome biogenesis disorder 6B 2010-08-01 no assertion criteria provided literature only

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