ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2442C>T (p.Phe814=) (rs145430946)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078921 SCV000110781 benign not specified 2013-03-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000356824 SCV000470510 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.
Invitae RCV001507118 SCV000754532 benign Zellweger syndrome 2020-12-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000859827 SCV001155137 likely benign not provided 2018-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000078921 SCV001363678 likely benign not specified 2019-06-06 criteria provided, single submitter clinical testing Variant summary: PEX1 c.2442C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0024 in 251264 control chromosomes, predominantly at a frequency of 0.0033 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is comparable to the estimated maximal expected allele frequency for a pathogenic variant in PEX1 causing Zellweger Syndrome (0.0039), suggesting this is likely a benign polymorphism. To our knowledge, no occurrence of c.2442C>T in individuals affected with Zellweger Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign (1x) and once as uncertain significance. An additional submitter (evaluation in 2013) cites the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.

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