ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2845C>T (p.Arg949Trp) (rs866184460)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000704649 SCV000833605 likely pathogenic Zellweger syndrome 2020-09-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 949 of the PEX1 protein (p.Arg949Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Zellweger syndrome (PMID: 21031596, 21844578). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 580960). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg949 amino acid residue in PEX1. Other variant(s) that disrupt this residue have been observed in individuals with PEX1-related conditions (PMID: 11389485), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Nilou-Genome Lab RCV001580539 SCV001810565 likely pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2021-07-22 criteria provided, single submitter clinical testing

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