ClinVar Miner

Submissions for variant NM_000310.3(PPT1):c.3G>A (p.Met1Ile) (rs386833645)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049604 SCV000220679 likely pathogenic Neuronal ceroid lipofuscinosis 1 2014-09-08 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000589397 SCV000696512 likely pathogenic Neuronal ceroid lipofuscinosis 2019-12-12 criteria provided, single submitter clinical testing Variant summary: PPT1 c.3G>A (p.Met1Ile) 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. Two of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247912 control chromosomes (gnomAD). c.3G>A has been reported in the literature in at least three individuals affected with late-infantile or juvenile-onset Neuronal Ceroid-Lipofuscinosis (Batten Disease; e.g. Das_1998, Hofmann_1999). These data indicate that the variant may be associated with disease. COS1 cells transfected with plasmids producing the mutant PPT1 protein expressed significantly lower levels of the enzyme, but were measured to have approximately 87.5% the PPT1 enzyme acitvity of wild-type cells (Lyly_2007), indicating the presence of functional enzyme, albeit at signifiantly lower levels compared to wild-type in cells with the initiation codon variant. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000049604 SCV001234611 pathogenic Neuronal ceroid lipofuscinosis 1 2019-08-01 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the PPT1 mRNA. The next in-frame methionine is located at codon 41. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with neuronal ceroid lipofuscinosis (PMID: 9664077, 11073228, 11440996). ClinVar contains an entry for this variant (Variation ID: 56193). This variant has been reported to affect PPT1 protein function (PMID:11440996). For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049604 SCV000082011 probable-pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Laboratory of Genetics in Ophthalmology,Institut Imagine RCV000049604 SCV001432260 pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided research

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