rs137852700

Variant names:

• chr1-40089495-G-A
• rs137852700
• NM_000310.4:c.451C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-40089495-G-A
• chr1-40089495-G-C
• chr1-40089495-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000310.4(PPT1):​c.451C>T​(p.Arg151*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000454 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: PPT1 NM_000310.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:33 O:1
• Conservation: PhyloP100: 7.12

Genes affected

PPT1 (HGNC:9325): (palmitoyl-protein thioesterase 1) The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-40089495-G-A is Pathogenic according to our data. Variant chr1-40089495-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40089495-G-A is described in Lovd as [Pathogenic]. Variant chr1-40089495-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPT1	NM_000310.4	c.451C>T	p.Arg151*	stop_gained	Exon 5 of 9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2	c.451C>T	p.Arg151*	stop_gained	Exon 5 of 8		NP_001350624.1
PPT1	NM_001142604.2	c.142C>T	p.Arg48*	stop_gained	Exon 2 of 6		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.451C>T	p.Arg151*	stop_gained	Exon 5 of 9		NM_000310.4	ENSP00000493153.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152066 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000243 AC: 61 AN: 251412 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135882

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000464 AC: 678 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.000433 AC XY: 315 AN XY: 727214

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000589

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152066 Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 19 AN XY: 74272

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000505 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:33 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:19 Other:1

Apr 29, 2021

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 27, 2014

Courtagen Diagnostics Laboratory, Courtagen Life Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Feb 24, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1, PM3 very strong -

-

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 25, 2020

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 19, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM3_VSTR,PM2_SUP -

Jun 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Pathogenic:9

Sep 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Apr 04, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM2, PM3, PS3, PS4, PVS1 -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis Pathogenic:2

Jul 06, 2011

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 09, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Inborn genetic diseases Pathogenic:1

Dec 06, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

PPT1-related disorder Pathogenic:1

Jul 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Neuronal Ceroid-Lipofuscinosis, Recessive Pathogenic:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.84
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852700; hg19: chr1-40555167; COSMIC: COSV65655640; COSMIC: COSV65655640;