ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.1579A>G (p.Thr527Ala) (rs144942544)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000584993 SCV000693241 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 syndrome 2020-12-05 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000584993 SCV001144897 likely benign not provided 2019-07-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
Nilou-Genome Lab RCV001083497 SCV001716352 likely benign Peroxisome biogenesis disorder 1A (Zellweger) 2021-05-18 criteria provided, single submitter clinical testing
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.

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