ClinVar Miner

Submissions for variant NM_000310.3(PPT1):c.29T>A (p.Leu10Ter) (rs137852699)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000715556 SCV000846385 pathogenic History of neurodevelopmental disorder 2016-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000009454 SCV000220758 likely pathogenic Ceroid lipofuscinosis neuronal 1 2014-09-30 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188716 SCV000854968 pathogenic not provided 2017-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000188716 SCV000242340 pathogenic not provided 2018-11-21 criteria provided, single submitter clinical testing The L10X nonsense variant in the PPT1 gene has been reported previously in several families with infantile or juvenile neuronal ceroid lipofuscinosis (NCL) who had a second pathogenic variant on the opposite allele (Mitchison et al., 1998; Miller et al., 2013). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional analysis showed L10X is associated with decreased mRNA and enzyme activity levels (Das et al., 2001; Miller et al., 2013).
Integrated Genetics/Laboratory Corporation of America RCV000009454 SCV000920081 pathogenic Ceroid lipofuscinosis neuronal 1 2017-12-15 criteria provided, single submitter clinical testing Variant summary: The PPT1 c.29T>A (p.Leu10X) variant results in a premature termination codon, predicted to cause a truncated or absent PPT1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One functional study determined less than 10% PPT activity in PBLs in a patient carrying this mutation (Mitchison_1998). One truncation downstream of this position has been classified as pathogenic by our laboratory (e.g. c.451C>T, p.Arg151X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 20/276316 control chromosomes (gnomAD) at a frequency of 0.0000724, which does not exceed the estimated maximal expected allele frequency of a pathogenic PPT1 variant (0.0007331). This variant has been reported in multiple patients with NCL, in both homozygotes and heterozygotes (Das_1998, Mitchison_1998, Stephenson_1999). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000009454 SCV000550823 pathogenic Ceroid lipofuscinosis neuronal 1 2016-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 10 (p.Leu10*) of the PPT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PPT1 are known to be pathogenic. This particular variant has been reported in the literature in individuals and families affected with juvenile or infantile neuronal ceroid lipofuscinosis (PMID: 9425237, 23539563, 9664077). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009454 SCV000029672 pathogenic Ceroid lipofuscinosis neuronal 1 1998-02-01 no assertion criteria provided literature only

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