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

gnomAD frequency: 0.00038  dbSNP: rs137852700

Total submissions: 33

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	2024-03-28	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