ClinVar Miner

Submissions for variant NM_000287.4(PEX6):c.2362G>A (p.Val788Met) (rs267608240)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672227 SCV000797314 likely pathogenic Peroxisome biogenesis disorder 4a (zellweger); Peroxisome biogenesis disorder 4B 2018-03-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780591 SCV000917988 likely pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2018-03-19 criteria provided, single submitter clinical testing Variant summary: PEX6 c.2362G>A (p.Val788Met) results in a conservative amino acid change located in the ATPase, AAA-type, core domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant is the last exonic nucleotide at an exon-intron junction, suggesting it may affect splicing. Four of five computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.8e-05 in 277372 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PEX6 causing Zellweger Syndrome (1.8e-05 vs 0.0019), allowing no conclusion about variant significance. The c.2362G>A variant has been reported in the literature in multiple individuals affected with Zellweger Syndrome, both as a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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