ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2114T>G (p.Leu705Trp)

dbSNP: rs863225084
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV001075286 SCV001240902 likely pathogenic Retinal dystrophy 2017-09-28 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV001810437 SCV002060251 uncertain significance Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B 2021-11-08 criteria provided, single submitter clinical testing 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.
Invitae RCV002517304 SCV003254622 uncertain significance Zellweger spectrum disorders 2022-08-22 criteria provided, single submitter clinical testing 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.
PreventionGenetics, part of Exact Sciences RCV003417729 SCV004109917 likely pathogenic PEX1-related condition 2023-11-27 criteria provided, single submitter clinical testing 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.
OMIM RCV000201290 SCV000256089 pathogenic Heimler syndrome 1 2015-10-01 no assertion criteria provided literature only

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