11-6617154-C-G

Position:

chr11-6617154-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000391.4(TPP1):c.509-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00126 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 0 hom. )

Consequence

TPP1
NM_000391.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:36O:2

Conservation

PhyloP100: 4.61

Variant links:

Genes affected

TPP1 (HGNC:2073): (tripeptidyl peptidase 1) This gene encodes a member of the sedolisin family of serine proteases. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates, and has weaker endopeptidase activity. It is synthesized as a catalytically-inactive enzyme which is activated and auto-proteolyzed upon acidification. Mutations in this gene result in late-infantile neuronal ceroid lipofuscinosis, which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome. [provided by RefSeq, Jul 2008]

TPP1 links:

TPP1 (HGNC:):

TPP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-6617154-C-G is Pathogenic according to our data. Variant chr11-6617154-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6617154-C-G is described in Lovd as [Pathogenic]. Variant chr11-6617154-C-G is described in Lovd as [Pathogenic]. Variant chr11-6617154-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPP1	NM_000391.4 linkuse as main transcript	c.509-1G>C		splice_acceptor_variant, intron_variant		ENST00000299427.12	NP_000382.3	O14773-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12 linkuse as main transcript	c.509-1G>C		splice_acceptor_variant, intron_variant		1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000941

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000402

AC:

101

AN:

251364

Hom.:

AF XY:

0.000368

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000836

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00134

AC:

1960

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

927

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00170

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000486

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000656

Hom.:

Bravo

AF:

0.000484

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.00119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:36Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 2

Pathogenic:17Other:1

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2018	The TPP1 c.509-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.509-1G>C variant is described as one of the two most common pathogenic variants found in individuals with the classical late-infantile form of neuronal ceroid-lipofuscinosis (LINCL), often found in a compound heterozygous state with the other common variant, p.Arg508Ter. Together they account for up to 60% of pathogenic variants in the TPP1 gene (Zhong et al. 1998; Sleat et al. 1999; Steinfeld et al. 2002). Across a selection of the literature, the c.509-1G>C variant was detected in a total of 56 individuals affected with LINCL, including in ten individuals in a homozygous state, in 42 individuals in a compound heterozygous state (two of whom were related) and in four individuals in a heterozygous state in whom a second variant was not detected due to incomplete screening methods. The variant was also found in a heterozygous state in one unaffected family member (Sleat et al. 1997; Zhong et al. 1998; Sleat et al. 1999; Steinfeld et al. 2002). The variant was absent from 32 control chromosomes and is reported at a frequency of 0.001047 in the European American population of the Exome Sequencing Project. The variant results in a significant reduction in TPP1 protease activity to between 0 - 10% of wild type depending on the sample type (Sleat et al. 1999; Steinfeld et al. 2002; Miller et al. 2013). Based on the collective evidence and the potential impact of splice acceptor variants, the c.509-1G>C variant is classified as pathogenic for neuronal ceroid-lipofuscinosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 18, 2019	NM_000391.3(TPP1):c.509-1G>C(aka IVS5-1G>C) is classified as pathogenic in the context of TPP1-related neuronal ceroid lipofuscinosis and is associated with the late-infantile form of the disease. Sources cited for classification include the following: PMID 9788728, 11339651 and 18684116. Classification of NM_000391.3(TPP1):c.509-1G>C(aka IVS5-1G>C) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£ -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 05, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Jul 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 22, 2016	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 06-16-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Oct 23, 2015	he c.509-1G>C variant is one of the most common pathogenic variants associated with LINCL and is found in both the homozygous or compound heterozygous state (Sleat DE et al., 1999; Zhong N et al., 1998; Kousi M et al., 2011). This variant was shown to segregate with disease in a non-consanguineous sib ship and in affected individuals who harbor this variant; enzyme activity in the leukocytes and fibroblasts was very low to almost absent respectively (Sun Y et al., 2013). Furthermore, the frequency of this variant is very low in the population database (1000 Genome, Exome Sequencing Project and ExAC). This locus is conserved across species and several computational algorithms predict the loss of splice-acceptor site in intron 5. Finally, several reputable clinical sources have classified this variant as pathogenic. In summary, the evidence meets our laboratoryâ€™s criteria for a Pathogenic classification -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Jan 13, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 08, 2024	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 2 (CLN2; MIM#204500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR studies showed intron 5 retention, resulting in p.(Val170Glyfs*29) which 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) (PMID: 23418007). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 113 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the most commonly reported variants in homozygous and compound heterozygous patients with CLN2 (ClinVar; PMID: 31283065; PMID: 32329550). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. The father has not been tested and the mother (VCGS # 20G001560) has tested negative for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 01, 2013	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 10, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2013	- -

not provided

Pathogenic:12

Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	TPP1: PVS1, PP1, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 20, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 16, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2022	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Different variant affecting the same splice site (c.509-1G>A) has been reported as pathogenic in the Human Gene Mutation Database and at GeneDx in association with NCL (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26026925, 26143525, 25976102, 26795593, 28335910, 10330339, 9788728, 26224725, 28554332, 9295267, 29056246, 29631617, 29655203, 30283815, 30548430, 31487502, 32631363, 31980526, 33845243, 12376936, 32298681, 31589614, 21990111, 23539563, 35054396, 34831035) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change affects an acceptor splice site in intron 5 of the TPP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TPP1 are known to be pathogenic (PMID: 10330339). This variant is present in population databases (rs56144125, gnomAD 0.08%). Disruption of this splice site has been observed in individuals with late-infantile neuronal ceroid lipofuscinosis (PMID: 9295267, 9788728, 10330339, 12376936). This variant is also known as c.523-1G>C, c.3556G>C or IVS5-1G>C. ClinVar contains an entry for this variant (Variation ID: 2644). 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. -

Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 26, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant classified as Pathogenic and reported on 07-28-2014 by Baylor Genetics. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Neuronal ceroid lipofuscinosis

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	May 03, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2017	Variant summary: The TPP1 c.509-1G>C variant (also known as G3556C) involves the alteration of a highly conserved nucleotide at canonical splice acceptor site in intron 5. 5/5 splice prediction tools predict abrogation of the splice-site. This variant was found in 43/121262 control chromosomes from ExAC at a frequency of 0.0003546, which does not exceed the estimated maximal expected allele frequency of a pathogenic TPP1 variant (0.002958). This variant is one of the most common pathogenic variants associated with LINCL and is found in both the homozygous and compound heterozygous state, including evidence of cosegregation with disease (Sleat_ 1999; Ju_2002; Worgall_2007). Enzyme activity in the in patients carrying this variant was very low to absent, suggesting it leads to loss of protein function (Sleat_1999). In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Autosomal recessive spinocerebellar ataxia 7

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2013

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2024

The c.509-1G>C intronic alteration consists of a G to C substitution one nucleotide before exon 6 of the TPP1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the C allele has an overall frequency of 0.04% (113/282698) total alleles studied. The highest observed frequency was 0.081% (105/129070) of European (non-Finnish) alleles. This alteration was detected in the homozygous state, and in conjunction with another alteration in TPP1, in multiple individuals with autosomal recessive TPP1-related neuronal ceroid lipofuscinosis (Zhong, 1998; Sleat, 1999; Steinfeld, 2002; Moore, 2008; Dy, 2015; Helbig, 2016; Bowling, 2017; Butler, 2017; Balciuniene, 2019; Costain, 2019; Amadori, 2020). This nucleotide position is highly conserved in available vertebrate species. In an assay testing TPP1 function, this variant showed a functionally abnormal result (Ma, 2021). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -

TPP1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2024

The TPP1 c.509-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant (also known as G3556C) has been reported as causative for neuronal ceroid lipofuscinosis in the homozygous and compound heterozygous states (Sleat et al. 1997. PubMed ID: 9295267; Sleat et al. 1999. PubMed ID: 10330339; Miller et al. 2013. PubMed ID: 23539563). This variant is reported in 0.081% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in TPP1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: -41

DS_AL_spliceai

0.96

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over