Submissions for variant NM_000466.3(PEX1):c.643_647del (p.Thr215fs)

dbSNP: rs786204544

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169257	SCV000220546	likely pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2014-07-24	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850395	SCV002179793	pathogenic	Zellweger spectrum disorders	2022-04-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr215Alafs*11) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 9398847, 16086329, 16141001, 21031596, 26387595, 31831025). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188897). This premature translational stop signal has been observed in individual(s) with PEX1-related conditions (PMID: 19105186). This variant is present in population databases (rs786204544, gnomAD 0.06%).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271442	SCV002555669	pathogenic	Peroxisome biogenesis disorder	2022-06-06	criteria provided, single submitter	clinical testing	Variant summary: PEX1 c.643_647delACCAA (p.Thr215AlafsX11) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 5.3e-06 in 190114 control chromosomes. c.643_647delACCAA has been reported in the literature in at least one individual affected with Zellweger Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003474902	SCV004203367	pathogenic	Heimler syndrome 1	2023-02-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031693	SCV005669738	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger); Heimler syndrome 1; Peroxisome biogenesis disorder 1B	2024-05-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947447	SCV004761910	pathogenic	PEX1-related disorder	2024-02-21	no assertion criteria provided	clinical testing	The PEX1 c.643_647del5 variant is predicted to result in a frameshift and premature protein termination (p.Thr215Alafs*11). This variant has been reported in an individual with Zellweger syndrome (Table 1, Yik et al. 2009. PubMed ID: 19105186). This variant is reported in 0.0057% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in PEX1 are expected to be pathogenic. This variant is interpreted as pathogenic.