ClinVar Miner

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

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000704649 SCV000833605 uncertain significance Peroxisome biogenesis disorder 1A (Zellweger) 2017-10-25 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 reported to be compound heterozygous in individuals affected with Zellweger syndrome (PMID: 21031596, 27469511, 21844578). This finding is consistent with autosomal recessive inheritance, and suggests that this variant may contribute to disease. 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. 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.

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