rs863225084
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_000466.3(PEX1):c.2114T>G(p.Leu705Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,568 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L705L) has been classified as Likely benign.
Frequency
Consequence
NM_000466.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX1 | NM_000466.3 | c.2114T>G | p.Leu705Trp | missense_variant | 13/24 | ENST00000248633.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.2114T>G | p.Leu705Trp | missense_variant | 13/24 | 1 | NM_000466.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251212Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135752
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461568Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727096
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
PEX1-related condition Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 27, 2023 | The PEX1 c.2114T>G variant is predicted to result in the amino acid substitution p.Leu705Trp. This variant was reported in compound heterozygous state with a PEX1 loss-of-function variant in an individual with Heimler syndrome (Ratbi et al 2015. PubMed ID: 26387595). This variant shows partial loss of function (around 60% of wild type) and therefore is assessed as a hypomorphic allele that would cause disease if in compound heterozygous state with a loss-of-function allele (Figure 4, Ratbi et al 2015. PubMed ID: 26387595). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. - |
Heimler syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2015 | - - |
Retinal dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 28, 2017 | - - |
Zellweger spectrum disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 705 of the PEX1 protein (p.Leu705Trp). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with Heimler syndrome (PMID: 26387595). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217428). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Peroxisome biogenesis disorder 1B;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 08, 2021 | NM_000466.2(PEX1):c.2114T>G(L705W) is a missense variant classified as a variant of uncertain significance in the context of peroxisome biogenesis disorder type 1. L705W has been observed in cases with relevant disease (PMID: 26387595). Functional assessments of this variant are available in the literature (PMID: 26387595). L705W has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, there is insufficient evidence to classify NM_000466.2(PEX1):c.2114T>G(L705W) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at