rs61750427
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000466.3(PEX1):āc.2966T>Cā(p.Ile989Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. I989I) has been classified as Likely benign.
Frequency
Consequence
NM_000466.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX1 | NM_000466.3 | c.2966T>C | p.Ile989Thr | missense_variant | 19/24 | ENST00000248633.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.2966T>C | p.Ile989Thr | missense_variant | 19/24 | 1 | NM_000466.3 | P1 | |
ENST00000658444.1 | n.3689A>G | non_coding_transcript_exon_variant | 2/2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000717 AC: 18AN: 251010Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135684
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461714Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727160
GnomAD4 genome ? AF: 0.0000459 AC: 7AN: 152358Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74512
ClinVar
Submissions by phenotype
Heimler syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Pathogenic, criteria provided, single submitter | research | Leeds Amelogenesis Imperfecta Research Group, University of Leeds | Oct 01, 2015 | Paper reports individual compound heterozygous for this variant - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2022 | 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. - |
Zellweger spectrum disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | 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. - |
Peroxisome biogenesis disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 18, 2023 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2022 | 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) - |
Peroxisome biogenesis disorder 1B;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at