ClinVar Miner

Submissions for variant NM_001127649.3(PEX26):c.2T>C (p.Met1Thr) (rs74315506)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000779366 SCV000915966 likely pathogenic Peroxisome biogenesis disorder 7A 2018-08-17 criteria provided, single submitter clinical testing The PEX26 c.2T>C (p.Met1?) variant is predicted to disrupt the initiator codon and thus may interfere with protein expression. This variant has been reported in two individuals with infantile Refsum disease, both of whom were compound heterozygous for this variant and the same missense variant (Matsumoto et al. 2003; Weller et al. 2005). Another variant (c.3T>C) that results in the same protein consequence has been reported in a compound heterozygous state in an individual with hearing loss and enamel defects, consistent with Heimler syndrome (Neuhaus et al. 2017). The p.Met1? variant was absent from 106 control chromosomes but is reported at a frequency of 0.000062 in the East Asian population of the Genome Aggregation Database. However, this frequency is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. Studies in patient and non-patient cells have demonstrated that the variant impairs protein function, including less effective recruitment of Pex1p-Pex6p complexes to peroxisomes and reduced peroxisomal protein import (Matsumoto et al. 2003; Weller et al. 2005; Furuki et al. 2006). Due to the potential impact of initiator codon variants and the available literature, the p.Met1? variant is classified as likely pathogenic for Zellweger syndrome spectrum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000002239 SCV000022397 pathogenic Peroxisome biogenesis disorder 7B 2003-08-01 no assertion criteria provided literature only

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