chr7-92499808-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000466.3(PEX1):c.2614C>T(p.Arg872Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000112 in 1,609,740 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R872R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000466.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX1 | NM_000466.3 | c.2614C>T | p.Arg872Ter | stop_gained | 16/24 | ENST00000248633.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.2614C>T | p.Arg872Ter | stop_gained | 16/24 | 1 | NM_000466.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000133 AC: 2AN: 150864Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251050Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135654
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1458876Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8AN XY: 725836
GnomAD4 genome AF: 0.0000133 AC: 2AN: 150864Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73486
ClinVar
Submissions by phenotype
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:3
Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The PEX1 c.2614C>T (p.R872*) nonsense variant is predicted to result in an aberrant or absent protein. This variant has been reported in the homozygous and compound heterozygous state in individuals with Zellweger spectrum disorder (PMID: 21031596; 12032265; 19105186; 20301621). - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Heimler syndrome 1 (MIM#234580), peroxisome biogenesis disorder 1A (Zellweger; MIM#214100) and peroxisome biogenesis disorder 1B (NALD/IRD; MIM#601539). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with Zellweger spectrum disorder and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 19105186). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Zellweger spectrum disorders Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Arg872*) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 21031596, 26387595, 31831025). This variant is present in population databases (rs61750422, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with PEX1-related conditions (PMID: 12032265, 19105186, 21846392). ClinVar contains an entry for this variant (Variation ID: 265395). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 08, 2020 | Has been reported previously in individuals with PEX1-related disorders (Preuss et al., 2002; Rosewich et al., 2005; Yik et al., 2009; Thoms et al., 2011); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 19105186, 21846392, 16141001, 12032265) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 23, 2021 | - - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 18, 2022 | ACMG classification criteria: PVS1, PS4, PM2 - |
Heimler syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 21, 2023 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 21, 2020 | Variant summary: PEX1 c.2614C>T (p.Arg872X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251050 control chromosomes. c.2614C>T has been reported in the literature in multiple individuals affected with Zellweger Syndrome with elevated VCLFA (very long chain fatty acid) levels (example, Preuss_2002, Yik_2009, Thoms_2011, Alshenaifi_2019). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Abnormality of metabolism/homeostasis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Peroxisome biogenesis disorder 1B;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at