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

gnomAD frequency: 0.00002  dbSNP: rs386833640

Total submissions: 6

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049599	SCV002279001	pathogenic	Neuronal ceroid lipofuscinosis 1	2025-01-21	criteria provided, single submitter	clinical testing	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). This variant is present in population databases (rs386833640, gnomAD 0.004%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 23772246; internal data). ClinVar contains an entry for this variant (Variation ID: 56188). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
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.
Fulgent Genetics, Fulgent Genetics	RCV000049599	SCV005648651	likely pathogenic	Neuronal ceroid lipofuscinosis 1	2024-04-11	criteria provided, single submitter	clinical testing
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.