Submissions for variant NM_000466.3(PEX1):c.2T>C (p.Met1Thr)

gnomAD frequency: 0.00002  dbSNP: rs766020928

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000412294	SCV000487623	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2016-05-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000410262	SCV000487624	pathogenic	Peroxisome biogenesis disorder 1B	2016-05-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174676	SCV001337909	pathogenic	Peroxisome biogenesis disorder	2020-01-10	criteria provided, single submitter	clinical testing	Variant summary: PEX1 c.2T>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 199938 control chromosomes (gnomAD). c.2T>C has been reported in the literature in multiple homozygous individuals affected with Zellweger Syndrome (ie. Ebberink_2010, Ghosh_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001232745	SCV001405313	pathogenic	Zellweger spectrum disorders	2022-11-30	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the PEX1 mRNA. The next in-frame methionine is located at codon 209. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371746). Disruption of the initiator codon has been observed in individuals with Zellweger spectrum disorder (PMID: 21031596, 28468868). This variant is present in population databases (rs766020928, gnomAD 0.01%).
Centogene AG - the Rare Disease Company	RCV001250203	SCV001424472	pathogenic	Peroxisome biogenesis disorder type 1A		criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000412294	SCV001760199	likely pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001232745	SCV002079359	pathogenic	Zellweger spectrum disorders	2017-03-17	no assertion criteria provided	clinical testing