Submissions for variant NM_000466.3(PEX1):c.1579A>G (p.Thr527Ala)

gnomAD frequency: 0.00217  dbSNP: rs144942544

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000584993	SCV000693241	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	PEX1: BP4
Eurofins Ntd Llc (ga)	RCV000591691	SCV000703814	likely benign	not specified	2016-11-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000660395	SCV000782475	uncertain significance	Peroxisome biogenesis disorder 1B	2016-08-21	criteria provided, single submitter	clinical testing
Invitae	RCV001391319	SCV001095996	likely benign	Zellweger spectrum disorders	2024-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000584993	SCV001144897	likely benign	not provided	2019-07-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001083497	SCV001324113	uncertain significance	Peroxisome biogenesis disorder 1A (Zellweger)	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000591691	SCV001363680	likely benign	not specified	2019-11-07	criteria provided, single submitter	clinical testing	Variant summary: PEX1 c.1579A>G (p.Thr527Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 248932 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PEX1 causing Zellweger Syndrome (0.0021 vs 0.0039). However, this frequency is significantly higher than the frequency of the most common pathogenic variant in PEX1 (c.2097dupT/p.Ile700TyrfsTer42, 0.00048 in gnomAD), suggesting the variant of interest is unlikely to be pathogenic. c.1579A>G has been reported in the literature in individuals affected with Zellweger Syndrome and retinal dystrophy without specified allele in trans (Ebberink_2010, Watson_2014). These reports do not provide unequivocal conclusions about association of the variant with Zellweger Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign (1x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab	RCV001083497	SCV001716352	likely benign	Peroxisome biogenesis disorder 1A (Zellweger)	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001578749	SCV001806049	likely benign	Heimler syndrome 1	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000660395	SCV001806050	likely benign	Peroxisome biogenesis disorder 1B	2021-07-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925755	SCV004741730	likely benign	PEX1-related disorder	2021-02-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000584993	SCV001553043	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PEX1 p.Thr527Ala variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs144942544), ClinVar (classified as likely benign by EGL Genetic Diagnostics and as a VUS by Mayo Clinic Genetic Testing Laboratories and CeGaT Praxis fuer Humangenetik Tuebingen). The variant was also identified in control databases in 587 of 280334 chromosomes at a frequency of 0.002094 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 458 of 128286 chromosomes (freq: 0.00357), Other in 13 of 7140 chromosomes (freq: 0.001821), South Asian in 48 of 30138 chromosomes (freq: 0.001593), Latino in 32 of 35238 chromosomes (freq: 0.000908), European (Finnish) in 19 of 25088 chromosomes (freq: 0.000757) and African in 17 of 24248 chromosomes (freq: 0.000701); it was not observed in the Ashkenazi Jewish, and East Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Thr527 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000584993	SCV001739559	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000584993	SCV001920595	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000584993	SCV001954907	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000584993	SCV001967429	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001391319	SCV002076903	likely benign	Zellweger spectrum disorders	2017-05-10	no assertion criteria provided	clinical testing