ClinVar Miner

Submissions for variant NM_000310.4(PPT1):c.413C>T (p.Ser138Leu)

gnomAD frequency: 0.00005  dbSNP: rs386833646
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049605 SCV000800709 uncertain significance Neuronal ceroid lipofuscinosis 1 2018-05-18 criteria provided, single submitter clinical testing
Invitae RCV000049605 SCV001208999 pathogenic Neuronal ceroid lipofuscinosis 1 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 138 of the PPT1 protein (p.Ser138Leu). This variant is present in population databases (rs386833646, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis 1 (PMID: 21990111, 30842224; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56194). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PPT1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000049605 SCV002518902 pathogenic Neuronal ceroid lipofuscinosis 1 2022-05-04 criteria provided, single submitter clinical testing
3billion RCV000049605 SCV002573094 likely pathogenic Neuronal ceroid lipofuscinosis 1 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). The variant is in trans with the other variant (NM_000310.4:c.433+1G>A). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.29). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PPT1-related disorder (PMID: 21990111). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003226183 SCV003922624 pathogenic Neuronal ceroid lipofuscinosis 2023-03-20 criteria provided, single submitter clinical testing Variant summary: PPT1 c.413C>T (p.Ser138Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes (gnomAD). c.413C>T has been reported in the literature in multiple individuals affected with rett syndrome, neurodevelopmental disabilities, progressive myoclonic epilepsy and epilepsy (example: Iwama_2019, Kim_2019, Zhang_2020 and Zhao_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000049605 SCV004204136 likely pathogenic Neuronal ceroid lipofuscinosis 1 2023-09-20 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049605 SCV000082012 probable-pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Natera, Inc. RCV000049605 SCV002085995 uncertain significance Neuronal ceroid lipofuscinosis 1 2020-02-05 no assertion criteria provided clinical testing

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