ClinVar Miner

Submissions for variant NM_000286.3(PEX12):c.744dup (p.Thr249fs) (rs61752108)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669254 SCV000793988 pathogenic Infantile Refsum's disease; Peroxisome biogenesis disorder 3A 2017-09-08 criteria provided, single submitter clinical testing
GeneDx RCV001008292 SCV001168060 likely pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing The c.744dupT variant in the PEX12 gene has been reported previously using alternate nomenclature (c.744_745insT) with another PEX12 variant in association with Zellweger syndrome (Chang et al., 1997; Chang and Gould, 1998; Ebberink et al., 2011). The c.744dupT variant causes a frameshift starting with codon Threonine 249, changes this amino acid to a Tyrosine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Thr249TyrfsX14. This variant is predicted to cause loss of normal protein function through protein truncation. The c.744dupT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.744dupT as a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV001174916 SCV001338351 likely pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2020-02-10 criteria provided, single submitter clinical testing Variant summary: PEX12 c.744dupT (p.Thr249TyrfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250122 control chromosomes (gnomAD). c.744dupT has been reported in the literature in individuals affected with Zellweger Syndrome (examples- Chang_1997, Ebberink_2010). These data indicate that the variant may be associated with disease. To our knowledge, there are no publications reporting experimental evidence assessing the impact of the variant on protein function. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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