ClinVar Genomic variation as it relates to human health

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 28367323, 21990111, 21704547, 24997880, 10649502, 31741823, 9664077)

The homozygous p.Arg164Ter variant in PPT1 was identified by our study in two siblings with neuronal ceroid lipofuscinosis. The p.Arg164Ter variant in PPT1 has been previously reported in four unrelated individuals with neuronal ceroid lipofuscinosis 1 (PMID: 31741823, PMID: 21990111, PMID: 10649502, PMID: 9664077), but has been identified in 0.005% (1/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386833649). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the four affected individuals previously reported (PMID: 31741823, PMID: 21990111, PMID: 10649502, PMID: 9664077), three were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 31741823, PMID: 21990111, PMID: 9664077, ClinVar Variation ID: 8904), and one was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 10649502, ClinVar Variation ID: 56217), and the affected siblings identified by our study were homozygotes, which increases the likelihood that the p.Arg164Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 56197) and has been interpreted as pathogenic by Invitae and the Shahid Beheshti University of Medical Sciences Genomic Research Center and as likely pathogenic by Counsyl. This nonsense variant leads to a premature termination codon at position 164, which is predicted to lead to a truncated or absent protein. Loss of function of the PPT1 gene is an established mechanism of autosomal recessive neuronal ceroid lipofuscinosis 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive neuronal ceroid lipofuscinosis 1. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong (Richards 2015).

This sequence change creates a premature translational stop signal (p.Arg164*) in the PPT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943, 21990111). This variant is present in population databases (rs386833649, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with neuronal ceroid lipofuscinosis (PMID: 9664077, 10649502). ClinVar contains an entry for this variant (Variation ID: 56197). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Converted during submission from probable-pathogenic to Likely pathogenic.

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.