ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2992C>T (p.Arg998Ter) (rs61750428)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000590014 SCV000696796 likely pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2016-11-18 criteria provided, single submitter clinical testing Variant summary: The PEX1 c.2992C>T (p.Arg998X) 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. A functional assay using patient cells showed that this variant leads significant reduction in synthesis of mRNA (Maxwell_2002). Truncations downstream of this position have been classified as pathogenic by laboratories in ClinVar (e.g. c.3505_3517delCAGTTGTTTTCAC, c.3693_3696delGTCA, p.Trp1250Ter, etc.). This variant was found in 1/119888 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX1 variant (0.003873). This variant has been reported in two patients with a confirmed dx of Zellweger syndrome. Taken together, this variant is classified as Likely Pathogenic variant.
Invitae RCV000818703 SCV000959329 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2018-10-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg998*) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs61750428, ExAC 0.002%). This variant has been observed in individuals affected with PEX1-related conditions (PMID: 12402331, 19105186). ClinVar contains an entry for this variant (Variation ID: 495880). 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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