ClinVar Miner

Submissions for variant NM_000310.4(PPT1):c.451C>T (p.Arg151Ter)

gnomAD frequency: 0.00038  dbSNP: rs137852700
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Total submissions: 33
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000188718 SCV000230905 pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory, Courtagen Life Sciences RCV000009455 SCV000236512 pathogenic Neuronal ceroid lipofuscinosis 1 2014-08-27 criteria provided, single submitter clinical testing
GeneDx RCV000188718 SCV000242342 pathogenic not provided 2022-09-07 criteria provided, single submitter clinical testing The R151* 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); Published functional studies demonstrate the variant results in significantly decreased PPT1 levels (Miller et al., 2015); 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; This variant is associated with the following publications: (PMID: 17261688, 11506414, 26990548, 34469436, 25574475, 23772246, 25525159, 21228398, 9733046, 10679943, 10649502, 19793312, 24082928, 23539563, 9425237, 31980526, 31589614, 21990111, 9664077, 25205113)
Illumina Laboratory Services, 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.
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
Genetic Services Laboratory, University of Chicago RCV000009455 SCV000596571 pathogenic Neuronal ceroid lipofuscinosis 1 2016-02-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000009455 SCV000611240 pathogenic Neuronal ceroid lipofuscinosis 1 2022-05-17 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000188718 SCV000614761 pathogenic not provided 2016-04-04 criteria provided, single submitter clinical testing
Invitae RCV000009455 SCV000640456 pathogenic Neuronal ceroid lipofuscinosis 1 2024-01-29 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. Loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943, 21990111). This variant is present in population databases (rs137852700, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with PPT1-related neuronal ceroid lipofusinosis (PMID: 9425237, 9664077, 21990111). ClinVar contains an entry for this variant (Variation ID: 8904). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Ambry Genetics RCV002316187 SCV000849768 pathogenic Inborn genetic diseases 2018-12-06 criteria provided, single submitter clinical testing The p.R151* pathogenic mutation (also known as c.451C>T), located in coding exon 5 of the PPT1 gene, results from a C to T substitution at nucleotide position 451. This changes the amino acid from an arginine to a stop codon within coding exon 5. This is the most common PPT1 mutation outside Finland and has been detected in multiple patients with neuronal ceroid lipofuscinosis (Das AK et al. J. Clin. Invest., 1998 Jul;102:361-70; Mitchison HM et al. Hum. Mol. Genet., 1998 Feb;7:291-7; Waliany S et al. Hum. Mutat., 2000 Feb;15:206-7). Ppt1 knockin mice carrying this mutation also recapitulated the neuronal ceroid lipofuscinosis phenotype (Bouchelion A et al. Ann Clin Transl Neurol, 2014 Dec;1:1006-23). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS RCV000009455 SCV000882526 likely pathogenic Neuronal ceroid lipofuscinosis 1 criteria provided, single submitter research
Baylor Genetics RCV000009455 SCV001162887 pathogenic Neuronal ceroid lipofuscinosis 1 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000009455 SCV001193929 pathogenic Neuronal ceroid lipofuscinosis 1 2019-12-09 criteria provided, single submitter clinical testing NM_000310.3(PPT1):c.451C>T(R151*) is classified as pathogenic in the context of PPT1-related neuronal ceroid lipofuscinosis, and is associated with the infantile form of the disease. Sources cited for classification include the following: PMID 23539563 and 9664077. Classification of NM_000310.3(PPT1):c.451C>T(R151*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Blueprint Genetics RCV000009455 SCV001426154 pathogenic Neuronal ceroid lipofuscinosis 1 2018-11-08 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000188718 SCV001447122 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
New York Genome Center RCV000009455 SCV001622972 pathogenic Neuronal ceroid lipofuscinosis 1 2020-06-25 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000009455 SCV002059844 pathogenic Neuronal ceroid lipofuscinosis 1 2021-04-29 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000009455 SCV002512217 pathogenic Neuronal ceroid lipofuscinosis 1 2021-05-07 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1, PM3 very strong
Institute of Human Genetics, University of Leipzig Medical Center RCV000009455 SCV002526721 pathogenic Neuronal ceroid lipofuscinosis 1 2023-09-19 criteria provided, single submitter clinical testing Criteria applied: PVS1,PM3_VSTR,PM2_SUP
Revvity Omics, Revvity RCV000009455 SCV003826615 pathogenic Neuronal ceroid lipofuscinosis 1 2023-02-28 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000009455 SCV003921783 pathogenic Neuronal ceroid lipofuscinosis 1 2021-05-07 criteria provided, single submitter clinical testing 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neuronal ceroid lipofuscinosis 1 (MIM#256730). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (69 heterozygotes, 0 homozygotes). (SP) 0701 - Other protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic, and have been observed in individuals with neuronal ceroid lipofuscinosis (ClinVar, Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and likely pathogenic in individuals with neuronal ceroid lipofuscinosis (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
3billion RCV000009455 SCV004013716 pathogenic Neuronal ceroid lipofuscinosis 1 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.024%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000008904 / PMID: 9425237). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences RCV003398477 SCV004111860 pathogenic PPT1-related disorder 2023-07-20 criteria provided, single submitter clinical testing The PPT1 c.451C>T variant is predicted to result in premature protein termination (p.Arg151*). This variant has been documented to be pathogenic for autosomal recessive neuronal ceroid lipofuscinoses (NCL), and its pathogenicity is supported by functional studies (Mitchison et al. 1998. PubMed ID: 9425237; Miller et al. 2013. PubMed ID: 23539563). It has been reported as the most commonly occurring PPT1 pathogenic variant worldwide (Kousi et al. 2012. PubMed ID: 21990111). This variant is reported in 0.050% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-40555167-G-A). Nonsense variants in PPT1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000188718 SCV004225813 pathogenic not provided 2022-07-11 criteria provided, single submitter clinical testing PP5, PM2, PM3, PS3, PS4, PVS1
OMIM RCV000009455 SCV000029673 pathogenic Neuronal ceroid lipofuscinosis 1 2015-01-01 no assertion criteria provided literature only
GeneReviews RCV000009455 SCV000086761 not provided Neuronal ceroid lipofuscinosis 1 no assertion provided literature only
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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000009455 SCV000734026 pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided clinical testing
Natera, Inc. RCV000009455 SCV001464018 pathogenic Neuronal ceroid lipofuscinosis 1 2020-09-16 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000188718 SCV001799183 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000188718 SCV001959409 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000188718 SCV001974852 pathogenic not provided no assertion criteria provided clinical testing

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