ClinVar Miner

Submissions for variant NM_000310.4(PPT1):c.287G>A (p.Cys96Tyr)

gnomAD frequency: 0.00002  dbSNP: rs386833640
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049599 SCV000800627 uncertain significance Neuronal ceroid lipofuscinosis 1 2017-11-26 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000049599 SCV001258865 uncertain significance Neuronal ceroid lipofuscinosis 1 2017-08-16 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV000049599 SCV002279001 likely pathogenic Neuronal ceroid lipofuscinosis 1 2023-06-16 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 56188). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 23772246). This variant is present in population databases (rs386833640, gnomAD 0.004%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 96 of the PPT1 protein (p.Cys96Tyr).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003230386 SCV003928936 uncertain significance not specified 2023-04-26 criteria provided, single submitter clinical testing Variant summary: PPT1 c.287G>A (p.Cys96Tyr) 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 1.2e-05 in 251464 control chromosomes (gnomAD). c.287G>A has been reported in the literature in individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Batten Disease), and one was reported as compound heterozygous with a pathogenic variant. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11589012, 24082928). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049599 SCV000082006 probable-pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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