ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2916del (p.Gly973fs) (rs61750426)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169435 SCV000220851 likely pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2014-11-05 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000414630 SCV000331721 pathogenic not provided 2018-08-03 criteria provided, single submitter clinical testing
GeneDx RCV000414630 SCV000491179 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing The c.2916delA variant in the PEX1 gene has been reported previously in association with Zellweger spectrum disorders when present in the homozygous state and when present with another disease-causing variant (Preuss et al., 2002; Thoms et al., 2011; Ebberink et al., 2011). This variant causes a frameshift starting with codon Glycine 973, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 16 of the new reading frame, denoted p.Gly973AlafsX16. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2916delA variant is observed in 11/126566 (0.009%) alleles from individuals of non-Finnish European background, in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.2916delA as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000588350 SCV000696795 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2017-03-09 criteria provided, single submitter clinical testing Variant summary: The PEX1 c.2916delA (p.Gly973Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent PEX1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/121358 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX1 variant (0.003873). Multiple publications cite the variant in individuals with Zellweger syndrome spectrum disorders, who were predominantly compound heterozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000169435 SCV000949205 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2018-10-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly973Alafs*16) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs61750426, ExAC 0.004%). This variant has been observed to be homozygous or in combination with another PEX1 variant in individuals affected with Zellweger syndrome spectrum (PMID: 12032265, 15542397, 21031596). ClinVar contains an entry for this variant (Variation ID: 189043). Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 9398847, 16086329, 16141001, 21031596). For these reasons, this variant has been classified as Pathogenic.

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