ClinVar Miner

Submissions for variant NM_000318.3(PEX2):c.782A>G (p.His261Arg)

gnomAD frequency: 0.00001  dbSNP: rs749956542
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674153 SCV000799440 uncertain significance Peroxisome biogenesis disorder 5A (Zellweger); Peroxisome biogenesis disorder 5B 2018-04-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000674153 SCV000895924 uncertain significance Peroxisome biogenesis disorder 5A (Zellweger); Peroxisome biogenesis disorder 5B 2021-09-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001855605 SCV002175018 uncertain significance Peroxisome biogenesis disorder 5A (Zellweger) 2022-06-13 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 261 of the PEX2 protein (p.His261Arg). This variant is present in population databases (rs749956542, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Zellweger syndrome spectrum (PMID: 21031596). ClinVar contains an entry for this variant (Variation ID: 557949). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265854 SCV002547970 uncertain significance not specified 2022-05-28 criteria provided, single submitter clinical testing Variant summary: PEX2 c.782A>G (p.His261Arg) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain (IPR001841) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251300 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.782A>G has been reported in the literature as a non-informative genotype (second allele not specified) in at-least one individual affected with Zellweger Syndrome (example, Ebberink_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Zellweger Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Personalized Medicine, Children's Hospital Los Angeles RCV003156108 SCV003845219 pathogenic See cases 2022-12-21 criteria provided, single submitter clinical testing

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