ClinVar Miner

Submissions for variant NM_000310.4(PPT1):c.541G>A (rs148412181)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169209 SCV000220464 likely pathogenic Neuronal ceroid lipofuscinosis 1 2014-06-27 criteria provided, single submitter literature only
Invitae RCV000169209 SCV000958226 pathogenic Neuronal ceroid lipofuscinosis 1 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 181 of the PPT1 protein (p.Val181Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs148412181, ExAC 0.03%). This variant has been observed in several individuals affected with neuronal ceroid lipofucinosis (NCL) (PMID: 9664077, 10649502, 15464427, 19302939, 30541466, 10191107) and has been observed to segregate with NCL in several families (PMID: 22387303, 23374165). ClinVar contains an entry for this variant (Variation ID: 188857). Experimental studies have shown that this missense change results in loss of PPT enzyme activity in a neuroblastoma cell line (PMID: 28878621) as well as in patient lymphoblasts (PMID: 9664077, 11440996). Variants that disrupt the p.Val181 amino acid residue in PPT1 have been observed in affected individuals (PMID: 21499717, 19302939). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000169209 SCV000965817 pathogenic Neuronal ceroid lipofuscinosis 1 2016-01-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169209 SCV001361117 pathogenic Neuronal ceroid lipofuscinosis 1 2019-03-11 criteria provided, single submitter clinical testing Variant summary: PPT1 c.541G>A (p.Val181Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 277014 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PPT1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (8.7e-05 vs 0.00073), allowing no conclusion about variant significance. c.541G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease, Das_1998, Santorelli_2013, Poyato_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein enzyme activity. The most pronounced variant effect results in <10% of normal activity (Das_1998, Poyato_2012). No 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 pathogenic.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV000169209 SCV001571358 pathogenic Neuronal ceroid lipofuscinosis 1 2021-04-12 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001723740 SCV001950330 pathogenic Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The p.Val181Met variant in PPT1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab ( Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3, PS3, PP1-M, PM1. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

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