ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2966T>C (p.Ile989Thr) (rs61750427)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Leeds Amelogenesis Imperfecta Research Group, University of Leeds RCV000240787 SCV000264808 pathogenic Deafness enamel hypoplasia nail defects 2015-10-01 criteria provided, single submitter research Paper reports individual compound heterozygous for this variant
Invitae RCV000695854 SCV000824376 uncertain significance Peroxisome biogenesis disorder 1A (Zellweger) 2018-05-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 989 of the PEX1 protein (p.Ile989Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs61750427, ExAC 0.07%). This variant has been reported in combination with a PEX1 pathogenic variant in several individuals affected with Zellweger syndrome (PMID: 27302843, 16088892). ClinVar contains an entry for this variant (Variation ID: 224325). 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. 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.
Baylor Genetics RCV001004317 SCV001163198 likely pathogenic Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175578 SCV001339211 uncertain significance not specified 2020-03-02 criteria provided, single submitter clinical testing Variant summary: PEX1 c.2966T>C (p.Ile989Thr) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 7.4e-05 in 282416 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PEX1 causing Zellweger Syndrome (7.4e-05 vs 0.0039), allowing no conclusion about variant significance. c.2966T>C has been reported in the literature in individuals (compound heterozygous and heterozygous) affected with Heimler syndrome (Gao_2019 , Smith_2016), non-syndromic hearing loss(Han_2019) and Zellweger syndrome (Maxwell_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic or uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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