ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs61750427
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Total submissions: 7
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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 Heimler syndrome 1 2015-10-01 criteria provided, single submitter research Paper reports individual compound heterozygous for this variant
Invitae RCV002229187 SCV000824376 pathogenic Zellweger spectrum disorders 2024-01-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 989 of the PEX1 protein (p.Ile989Thr). This variant is present in population databases (rs61750427, gnomAD 0.1%). This missense change has been observed in individual(s) with Zellweger syndrome (PMID: 16088892, 27302843; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 224325). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PEX1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004317 SCV001163198 likely pathogenic Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003226251 SCV001339211 likely pathogenic Peroxisome biogenesis disorder 2023-03-18 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 7.2e-05 in 251010 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PEX1 causing Zellweger Syndrome (7.2e-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, Thomas_2020, Chen_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, the reported evidence does not allow for convincing conclusions about the variant effect (Maxwell_2005). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx RCV002251446 SCV002521981 pathogenic not provided 2022-02-01 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27302843, 16086329, 31374812, 32203225, 16088892, 31054281, 30733538, 31831025, Parsamanesh2021[paper], 33708531, 34513757)
Ambry Genetics RCV002515571 SCV003551429 likely pathogenic Inborn genetic diseases 2022-03-28 criteria provided, single submitter clinical testing The c.2966T>C (p.I989T) alteration is located in exon 19 (coding exon 19) of the PEX1 gene. This alteration results from a T to C substitution at nucleotide position 2966, causing the isoleucine (I) at amino acid position 989 to be replaced by a threonine (T). Based on data from gnomAD, the C allele has an overall frequency of 0.01% (21/282416) total alleles studied. The highest observed frequency was 0.11% (21/19942) of East Asian alleles. This alteration was detected in trans with other PEX1 disease-causing alterations in multiple unrelated individuals with PEX1-related peroxisome biogenesis spectrum disorder (Thomas, 2020; Gao, 2019; Smith, 2016; Chen, 2021; Maxwell, 2005). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics RCV000240787 SCV004203265 likely pathogenic Heimler syndrome 1 2023-10-20 criteria provided, single submitter clinical testing

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