VCV000008904.52 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(33)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 8904 Accession: VCV000008904.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.2 1: 40089495 (GRCh38) [ NCBI UCSC ] 1: 40555167 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 1, 2013	Jul 23, 2024	Mar 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000310.4:c.451C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000301.1:p.Arg151Ter	nonsense
NM_001142604.2:c.142C>T	NP_001136076.1:p.Arg48Ter	nonsense
NM_001363695.2:c.451C>T	NP_001350624.1:p.Arg151Ter	nonsense
NC_000001.11:g.40089495G>A
NC_000001.10:g.40555167G>A
NG_009192.1:g.12976C>T
LRG_690:g.12976C>T
LRG_690t1:c.451C>T	LRG_690p1:p.Arg151Ter

... more HGVS ... less HGVS

Protein change

R151*, R48*

Other names

p.R151*:CGA>TGA
451C-T

Canonical SPDI

NC_000001.11:40089494:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00033

The Genome Aggregation Database (gnomAD) 0.00038

Links

ClinGen: CA316936 OMIM: 600722.0006 OMIM: 600722.0008 dbSNP: rs137852700 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PPT1		-	-	GRCh38 GRCh37	695	723

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Neuronal ceroid lipofuscinosis 1	Pathogenic/Likely pathogenic (19)	criteria provided, multiple submitters, no conflicts	Mar 28, 2024	RCV000009455.53
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Sep 7, 2022	RCV000188718.28
Neuronal Ceroid-Lipofuscinosis, Recessive	Pathogenic (1)	criteria provided, single submitter	Jun 14, 2016	RCV000352109.13
Neuronal ceroid lipofuscinosis	Pathogenic (2)	criteria provided, single submitter	Mar 9, 2017	RCV000583336.9
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Dec 6, 2018	RCV002316187.9
PPT1-related disorder	Pathogenic (1)	criteria provided, single submitter	Jul 20, 2023	RCV003398477.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 09, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511448.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Pathogenic (Feb 24, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ceroid lipofuscinosis, neuronal, 1 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000596571.1 First in ClinVar: Dec 06, 2015 Last updated: Dec 06, 2015
Pathogenic (Mar 09, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696513.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018	Publications: PubMed (3) PubMed: 25574475‚ 9664077‚ 9425237 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 25, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000230905.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 9425237 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PPT1 Number of individuals with the variant: 2 Sex: mixed
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Neuronal ceroid lipofuscinosis 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS Accession: SCV000882526.1 First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 Comment: Nonsense variant	Family history: no Age: 0-9 years Sex: male Tissue: blood Secondary finding: no Method: whole exome sequencing; PCR; sanger sequencing
Pathogenic (Dec 09, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193929.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020	Publications: PubMed (2) PubMed: 23539563‚ 9664077 Comment: 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 … (more) 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. (less)
Pathogenic (Nov 08, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001426154.1 First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447122.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Spasticity (present) , Developmental regression (present) , Severe muscular hypotonia (present) Sex: male
Pathogenic (Jun 25, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: inherited	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001622972.1 First in ClinVar: May 20, 2021 Last updated: May 20, 2021	Clinical Features: Generalized-onset seizure (present) , Delayed speech and language development (present) , Headache (present) Secondary finding: no
Pathogenic (May 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611240.2 First in ClinVar: Dec 06, 2015 Last updated: Dec 31, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: yes Allele origin: unknown	3billion Accession: SCV004013716.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (1) PubMed: 9425237 Comment: 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 … (more) 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. (less) Clinical Features: Delayed ability to walk (present) , Tremor (present) , Abnormal muscle tone (present) , Alopecia (present)
Pathogenic (Jul 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PPT1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004111860.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Feb 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003826615.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Aug 27, 2014)	criteria provided, single submitter (Courtagen Life Sciences Classifications) Method: clinical testing	Ceroid lipofuscinosis, neuronal, 1 Affected status: unknown Allele origin: germline	Courtagen Diagnostics Laboratory, Courtagen Life Sciences Accession: SCV000236512.2 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015
Pathogenic (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Neuronal Ceroid-Lipofuscinosis, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000357396.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (8) PubMed: 9425237‚ 9664077‚ 11506414‚ 17261688‚ 23539563‚ 23772246‚ 25574475‚ 25205113 Comment: 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), … (more) 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. (less)
Pathogenic (Apr 04, 2016)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000614761.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (15) PubMed: 9425237‚ 10649502‚ 11506414‚ 19793312‚ 24082928‚ 10679943‚ 9664077‚ 9733046‚ 25574475‚ 17261688‚ 25205113‚ 21228398‚ 23772246‚ 23539563‚ 25525159
Pathogenic (Apr 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059844.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (May 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512217.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PVS1, PM3 very strong Geographic origin: Brazil
Pathogenic (Sep 07, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242342.13 First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023	Comment: 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, … (more) 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) (less)
Pathogenic (Sep 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002526721.3 First in ClinVar: Jun 24, 2022 Last updated: Nov 04, 2023	Comment: Criteria applied: PVS1,PM3_VSTR,PM2_SUP Clinical Features: Developmental regression (present) , Hypotonia (present) , Severe global developmental delay (present) , Spasticity (present) , Global developmental delay (present) Sex: male
Pathogenic (Jul 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004225813.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (6) PubMed: 10679943‚ 11440996‚ 25205113‚ 25574475‚ 9425237‚ 9664077 Comment: PP5, PM2, PM3, PS3, PS4, PVS1 Number of individuals with the variant: 1
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000640456.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 28492532‚ 10679943‚ 21990111‚ 9425237‚ 9664077 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 06, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000849768.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 10649502‚ 11440996‚ 25574475‚ 9425237‚ 9664077 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001162887.2 First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV003921783.2 First in ClinVar: May 06, 2023 Last updated: Jul 23, 2024	Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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 (less)
Pathogenic (Jan 01, 2015)	no assertion criteria provided Method: literature only	CEROID LIPOFUSCINOSIS, NEURONAL, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029673.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 06, 2015	Publications: PubMed (5) PubMed: 9425237‚ 9664077‚ 11506414‚ 17261688‚ 25205113 Comment on evidence: In 7 of 22 disease chromosomes from 11 patients with juvenile-onset CLN1 (256730), Mitchison et al. (1998) found an arg151-to-ter (R151X) nonsense mutation in the … (more) In 7 of 22 disease chromosomes from 11 patients with juvenile-onset CLN1 (256730), Mitchison et al. (1998) found an arg151-to-ter (R151X) nonsense mutation in the PPT1 gene. In each case it was found in compound heterozygous state with a missense mutation. In 29 U.S. and Canadian families with PPT1 deficiency, Das et al. (1998) demonstrated that the R151X mutation accounted for 40% of the alleles and was associated with severe disease in homozygous state. See also 600722.0009 and van Diggelen et al. (2001), and 600722.0010 and Ramadan et al. (2007). Miller et al. (2015) generated a transgenic mouse model homozygous for the common R151X PPT1 mutation. Mutant PPT1 was significantly decreased in multiples tissues, consistent with nonsense-mediated mRNA decay, and PPT1 enzyme activity in homozygous mice was 1.7 to 3.1% of controls. The phenotype of the mutant mice recapitulated that observed in humans, including impaired motor function, decreased exploratory behavior, accumulation of autofluorescent material in the brain, and widespread astrogliosis and microglial activation throughout the brain. Intraperitoneal injection of the read-through drug ataluren (PTC124) increased PPT1 enzyme activity and protein levels in the liver, but not in the brain. Higher dosages of ataluren resulted in increased PPT1 activity in the brain, but caused a paradoxical decrease of PPT1 activity in the liver. The study provided proof of principle of the potential use of read-through drugs in the treatment of the disorder resulting from this specific mutation. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734026.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001464018.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001799183.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959409.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001974852.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Jul 06, 2011)	no assertion criteria provided Method: clinical testing	Neuronal ceroid lipofuscinosis Affected status: yes Allele origin: germline	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000692331.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018
not provided (-)	no classification provided Method: literature only	Neuronal ceroid lipofuscinosis 1 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000086761.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 9664077‚ 20301601 BookShelf: NBK1428 BookShelf: NBK1428
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Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy.	Miller JN	Human molecular genetics	2015	PMID: 25205113
Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype.	Bouchelion A	Annals of clinical and translational neurology	2014	PMID: 25574475
Atypical juvenile neuronal ceroid lipofuscinosis: A report of three cases.	Setty G	Journal of pediatric neurosciences	2013	PMID: 24082928
Novel CLN1 mutation with atypical juvenile neuronal ceroid lipofuscinosis.	Khan A	Journal of pediatric neurosciences	2013	PMID: 23772246
The role of nonsense-mediated decay in neuronal ceroid lipofuscinosis.	Miller JN	Human molecular genetics	2013	PMID: 23539563
Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2013	PMID: 20301601
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses.	Kousi M	Human mutation	2012	PMID: 21990111
Carrier testing for severe childhood recessive diseases by next-generation sequencing.	Bell CJ	Science translational medicine	2011	PMID: 21228398
An integrated strategy for the diagnosis of neuronal ceroid lipofuscinosis types 1 (CLN1) and 2 (CLN2) in eleven Latin American patients.	Kohan R	Clinical genetics	2009	PMID: 19793312
Adult neuronal ceroid lipofuscinosis caused by deficiency in palmitoyl protein thioesterase 1.	Ramadan H	Neurology	2007	PMID: 17261688
Adult neuronal ceroid lipofuscinosis with palmitoyl-protein thioesterase deficiency: first adult-onset patients of a childhood disease.	van Diggelen OP	Annals of neurology	2001	PMID: 11506414
Biochemical analysis of mutations in palmitoyl-protein thioesterase causing infantile and late-onset forms of neuronal ceroid lipofuscinosis.	Das AK	Human molecular genetics	2001	PMID: 11440996
Detection of eight novel palmitoyl protein thioesterase (PPT) mutations underlying infantile neuronal ceroid lipofuscinosis (INCL;CLN1).	Salonen T	Human mutation	2000	PMID: 10679943
Identification of three novel mutations of the palmitoyl-protein thioesterase-1 (PPT1) gene in children with neuronal ceroid-lipofuscinosis.	Waliany S	Human mutation	2000	PMID: 10649502
Sharing of PPT mutations between distinct clinical forms of neuronal ceroid lipofuscinoses in patients from Scotland.	Munroe PB	Journal of medical genetics	1998	PMID: 9733046
Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S.	Das AK	The Journal of clinical investigation	1998	PMID: 9664077
Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits.	Mitchison HM	Human molecular genetics	1998	PMID: 9425237
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PPT1	-	-	-	-
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Text-mined citations for rs137852700 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137852700 ...