NM_000391.4:c.509-1G>C

Variant names:

• chr11-6617154-C-G
• rs56144125
• NM_000391.4:c.509-1G>C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1 PM2 PP5_Very_Strong BS1_Supporting

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:36 O:2
• Conservation: PhyloP100: 4.61

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 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].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00134 (1960/1461866) while in subpopulation NFE AF= 0.0017 (1895/1111994). AF 95% confidence interval is 0.00164. There are 0 homozygotes in gnomad4_exome. There are 927 alleles in male gnomad4_exome subpopulation. Median coverage is 41. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4	c.509-1G>C		splice_acceptor_variant, intron_variant	Intron 5 of 12	ENST00000299427.12	NP_000382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12	c.509-1G>C		splice_acceptor_variant, intron_variant	Intron 5 of 12	1	NM_000391.4	ENSP00000299427.6

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152114 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000368 AC XY: 50 AN XY: 135878

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.: 0 Cov.: 41 AF XY: 0.00127 AC XY: 927 AN XY: 727242

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: 74 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74308

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.: 0

Bravo AF: 0.000484

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000600

EpiControl AF: 0.00119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:36 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 2 Pathogenic:17 Other:1

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Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2013

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Aug 14, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 05, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP3. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 18, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.‚Äã -

Sep 21, 2015

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 08, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2014

Courtagen Diagnostics Laboratory, Courtagen Life Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 laboratory’s criteria for a Pathogenic classification -

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Feb 10, 2015

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 22, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2021

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 08, 2024

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 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 -

not provided Pathogenic:12

Mar 13, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TPP1: PVS1, PP1, PS3:Supporting -

Feb 16, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Feb 16, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 Pathogenic:2 Other:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Apr 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis Pathogenic:2

May 03, 2012

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 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 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

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Jul 01, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
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

Other links and lift over

dbSNP: rs56144125; hg19: chr11-6638385; COSMIC: COSV99067420; COSMIC: COSV99067420;