ClinVar Miner

Submissions for variant NM_000310.3(PPT1):c.451C>T (p.Arg151Ter) (rs137852700)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000718904 SCV000849768 pathogenic History of neurodevelopmental disorder 2017-12-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Deficient protein function by in vitro/ex vivo assay,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Athena Diagnostics Inc RCV000188718 SCV000614761 pathogenic not provided 2016-04-04 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000188718 SCV000511448 pathogenic not provided 2017-02-09 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000583336 SCV000692331 pathogenic Neuronal ceroid lipofuscinosis 2011-07-06 no assertion criteria provided clinical testing
Counsyl RCV000009455 SCV000678084 pathogenic Ceroid lipofuscinosis neuronal 1 2015-06-13 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000009455 SCV000236512 pathogenic Ceroid lipofuscinosis neuronal 1 2014-08-27 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000009455 SCV000734026 pathogenic Ceroid lipofuscinosis neuronal 1 no assertion criteria provided clinical testing
Diagnostics Division,Centre for DNA Fingerprinting and Diagnostics RCV000009455 SCV000882526 likely pathogenic Ceroid lipofuscinosis neuronal 1 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188718 SCV000230905 pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing
Fulgent Genetics RCV000009455 SCV000611240 pathogenic Ceroid lipofuscinosis neuronal 1 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000188718 SCV000242342 pathogenic not provided 2018-10-15 criteria provided, single submitter clinical testing The R151X nonsense variant is the most common pathogenic variant in the PPT1 gene worldwide and has been reported previously in association with infantile, late-infantile, and juvenile neuronal ceroid lipofuscinosis (Mitchison et al., 1998; Das et al., 1998; Kousi et al., 2012). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
GeneReviews RCV000009455 SCV000086761 pathologic Ceroid lipofuscinosis neuronal 1 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000009455 SCV000596571 pathogenic Ceroid lipofuscinosis neuronal 1 2016-02-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000352109 SCV000357396 pathogenic Neuronal Ceroid-Lipofuscinosis, Recessive 2016-06-14 criteria provided, single submitter clinical testing Across a selection of the available literature, the c.451C>T (p.Arg151Ter) stop-gained variant has been identified in a total of 27 patients with neuronal ceroid-lipofuscinosis (NCL), including in a homozygous state in six patients, all with a severe phenotype, and in a compound heterozygous state with a second variant in 21 patients (Mitchison et al. 1998; Das et al. 1998; van Diggelen et al. 2001; Ramadan et al. 2007; Khan et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. PPT1 enzyme activity levels are significantly reduced in NCL patients carrying the p.Arg151Ter variant when compared to controls (Mitchison et al. 1998; van Diggelen et al. 2001; Ramadan et al. 2007; Miller et al. 2013; Khan et al. 2013). Miller et al. (2013) suggests that the degradation of mRNAs is a result of nonsense-mediated decay. Transgenic knock-in mouse models homozygous for the p.Arg151Ter variant recapitulate the NCL phenotype (Bouchelion et al. 2014; Miller et al. 2015). Due to the potential impact of stop-gained variants and the evidence in the literature, the p.Arg151Ter variant is classified as pathogenic for autosomal recessive neuronal ceroid-lipofuscinosis.
Integrated Genetics/Laboratory Corporation of America RCV000583336 SCV000696513 pathogenic Neuronal ceroid lipofuscinosis 2017-03-09 criteria provided, single submitter clinical testing Variant summary: The c.451C>T (p.Arg151*) in PPT1 gene is a nonsense change predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This prediction was confirmed by Das (1998) who showed undetectable levels of PPT protein in patients homozygous for c.451C>T. The variant is present in the large control population dataset of ExAC at a frequency 0.0001732 (21 / 121256chrs tested). This frequency does not exceed the maximal expected frequency of a pathogenic allele (0.0007) in this gene. The variant has been reported in multiple affected individuals with histologically and enzymatically confirmed dx of NCL. In addition, multiple reputable databases/clinical laboratories cite the variant as Pathogenic. Taking together, the variant of interest was classified as Pathogenic.
Invitae RCV000009455 SCV000640456 pathogenic Ceroid lipofuscinosis neuronal 1 2018-05-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg151*) in the PPT1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs137852700, ExAC 0.03%). This is the most common pathogenic variant reported in individuals affected with PPT1-related neuronal ceroid lipofusinosis (PMID: 9425237, 9664077, 21990111). ClinVar contains an entry for this variant (Variation ID: 8904). Loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009455 SCV000029673 pathogenic Ceroid lipofuscinosis neuronal 1 2015-01-01 no assertion criteria provided literature only

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