ClinVar Miner

Submissions for variant NM_000287.4(PEX6):c.821C>T (p.Pro274Leu) (rs61753219)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622824 SCV000741077 pathogenic Inborn genetic diseases 2015-10-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Counsyl RCV000666553 SCV000790861 likely pathogenic Peroxisome biogenesis disorder 4a (zellweger); Peroxisome biogenesis disorder 4B 2017-04-12 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network,NIH RCV000735222 SCV000863430 likely pathogenic Peroxisome biogenesis disorder 4B 2018-09-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193476 SCV001362344 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2019-07-11 criteria provided, single submitter clinical testing Variant summary: PEX6 c.821C>T (p.Pro274Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251460 control chromosomes. c.821C>T has been reported in the literature in multiple individuals affected with Zellweger Syndrome (Steinberg_2004,Ebberink_2010) and Heimler Syndrome (Ratbi_2015). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (Ratbi_2015, Falkenberg_2017). The most pronounced variant effect results in <10% of normal peroxisomal activity. Four ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001193476 SCV001372601 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2019-11-03 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 274 of the PEX6 protein (p.Pro274Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs61753219, ExAC 0.003%). This variant has been observed to be homozygous in or in combination with another PEX6 variant in several individuals with clinical features of Zellweger Syndrome Spectrum (PMID: 26387595, 19877282, 15542397, 24016303). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been observed to segregate with clinical features of Zellweger Syndrome Spectrum in a family (PMID: 26387595). ClinVar contains an entry for this variant (Variation ID: 217424). This variant has been reported to affect PEX6 protein function (PMID: 26387595, 29220678). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000201297 SCV000256084 pathogenic Heimler syndrome 2 2015-10-01 no assertion criteria provided literature only

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