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

gnomAD frequency: 0.00003  dbSNP: rs61750427

Total submissions: 7

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