ClinVar Miner

Submissions for variant NM_000310.4(PPT1):c.125G>A (p.Gly42Glu)

dbSNP: rs386833631
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049590 SCV000220645 likely pathogenic Neuronal ceroid lipofuscinosis 1 2014-08-28 criteria provided, single submitter literature only
Invitae RCV000049590 SCV003523270 uncertain significance Neuronal ceroid lipofuscinosis 1 2022-09-01 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 42 of the PPT1 protein (p.Gly42Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077). ClinVar contains an entry for this variant (Variation ID: 56179). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PPT1 function (PMID: 11440996). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003317067 SCV004020550 likely pathogenic Neuronal ceroid lipofuscinosis 2023-06-13 criteria provided, single submitter clinical testing Variant summary: PPT1 c.125G>A (p.Gly42Glu) 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' acceptor site and two predict the variant weakens the 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251424 control chromosomes (gnomAD). c.125G>A has been reported in the literature as a compound heterozygous genotype in two siblings affected with infantile onset Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Das_1998, Hofmann_1999). These data indicate that the variant may be associated with disease. Additionally, a functional study found the variant showed no detectable instrinsic enzyme activity in vitro, with <2% activity of the WT protein (Das_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11440996, 9664077, 10191107). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000049590 SCV004204148 likely pathogenic Neuronal ceroid lipofuscinosis 1 2023-07-26 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049590 SCV000081997 probable-pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.