ClinVar Miner

Submissions for variant NM_000310.4(PPT1):c.490C>T (p.Arg164Ter)

gnomAD frequency: 0.00001  dbSNP: rs386833649
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049608 SCV000220640 likely pathogenic Neuronal ceroid lipofuscinosis 1 2014-08-26 criteria provided, single submitter literature only
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000049608 SCV000746400 pathogenic Neuronal ceroid lipofuscinosis 1 2017-12-18 criteria provided, single submitter clinical testing
Invitae RCV000049608 SCV001590137 pathogenic Neuronal ceroid lipofuscinosis 1 2024-01-08 criteria provided, single submitter clinical testing 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000049608 SCV003761274 pathogenic Neuronal ceroid lipofuscinosis 1 2023-01-25 criteria provided, single submitter curation 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).
Baylor Genetics RCV000049608 SCV004204133 pathogenic Neuronal ceroid lipofuscinosis 1 2023-10-05 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049608 SCV000082015 probable-pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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