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 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2019-05-31 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. At least one publication, Matsumoto_2001, reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 1.6e-05 in 251656 control chromosomes (gnomAD). The variant, c.2362G>A, has been reported in the literature in multiple individuals affected with Zellweger Syndrome, both as a homozygous and compound heterozygous allele. (Steinberg_2004, Krause_2009, Ebberink_2010, Lusebrink_2016). 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 (Lusebrink_2016). One ClinVar submission from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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