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

gnomAD frequency: 0.00216  dbSNP: rs145430946

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078921	SCV000110781	benign	not specified	2013-03-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001507118	SCV000754532	benign	Zellweger spectrum disorders	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000859827	SCV001155137	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	PEX1: BP4, BP7
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.
Clinical Genetics, Academic Medical Center	RCV000859827	SCV001919294	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000859827	SCV001963868	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001507118	SCV002076865	likely benign	Zellweger spectrum disorders	2017-05-10	no assertion criteria provided	clinical testing