rs119455955

chr11-6617040-G-A

Variant summary

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

The NM_000391.4(TPP1):c.622C>T(p.Arg208Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,613,976 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R208R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: TPP1 NM_000391.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:29 O:1
• Conservation: PhyloP100: 3.17

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 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 11-6617040-G-A is Pathogenic according to our data. Variant chr11-6617040-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6617040-G-A is described in Lovd as [Pathogenic]. Variant chr11-6617040-G-A is described in Lovd as [Pathogenic]. Variant chr11-6617040-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4	c.622C>T	p.Arg208Ter	stop_gained	6/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.622C>T	p.Arg208Ter	stop_gained	6/13	1	NM_000391.4	P1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000471

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000223 AC: 56 AN: 251232 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000311 AC: 455 AN: 1461860 Hom.: 0 Cov.: 42 AF XY: 0.000329 AC XY: 239 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000386

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74314

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000414 Hom.: 0

Bravo AF: 0.000230

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:29 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 2 Pathogenic:13 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000391.3(TPP1):c.622C>T(R208*) is classified as pathogenic in the context of TPP1-related neuronal ceroid lipofuscinosis and is associated with the late-infantile form of this disease. Sources cited for classification include the following: PMID 15317752, 9788728, 21990111, 23539563 and 10330339. Classification of NM_000391.3(TPP1):c.622C>T(R208*) 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.‚Äã -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Nov 07, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 09, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 19, 1997	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2018	The TPP1 c.622C>T (p.Arg208Ter) variant is a stop-gained variant predicted to result in in a premature termination of the protein. The p.Arg206Ter variant has been reported in at least five studies in which it was identified in 31 affected individuals, including in six in a homozygous state and in 25 in a compound heterozygous state, two of whom are siblings (Sleat et al. 1997; Sleat et al. 1999; Barisić et al. 2003; Helbig et al. 2016). Thirty of the individuals were diagnosed with neuronal ceroid-lipofuscinoses with one compound heterozygote presenting with a diagnosis of focal epilepsy (Helbig et al. 2016). In one study, the p.Arg208Ter variant accounted for 28% of disease alleles. The variant was absent from four controls but is reported at a frequency of 0.000619 in the Other population of the Genome Aggregation Database. Functional studies in HEK and CHO cells transfected with the variant showed that the variant resulted in enzymatic activity of 3.3% and 2.8% respectively compared to 100% in wild type (Steinfeld et al. 2004). A mouse model created by Geraets et al. (2017) mimicked the human disease very closely. TPP1 activity was found to be reduced by at least 90% compared to the wild type mice with Cln2 transcript levels reduced by 60-90% in tissue samples from a range of organs. Based on the collective evidence, the p.Arg208Ter 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	MGZ Medical Genetics Center	Jan 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 25, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2021	Published functional studies demonstrate damaging effects, including a reduction in transcript abundance and enzyme activity (Geraets et al., 2017); 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: 19793312, 23539563, 12363103, 9788728, 21940688, 11071145, 12414822, 12796825, 18283468, 26795593, 29631617, 29554876, 15317752, 25525159, 20301601, 10665500, 18684116, 21990111, 9295267, 10330339, 12950156, 28464005, 29655203, 30541466, 30945278, 31170314, 31122803, 31980526, 32412666, 33845243, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Arg208*) in the TPP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPP1 are known to be pathogenic (PMID: 10330339). This variant is present in population databases (rs119455955, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9295267, 10330339, 23539563, 26026925, 26795593). ClinVar contains an entry for this variant (Variation ID: 2643). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TPP1: PM3:Very Strong, PVS1, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 16, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 24, 2023	PM2, PS3, PS4_moderate, PVS1 -

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

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 31, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Neuronal ceroid lipofuscinosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2016	Variant summary: The TPP1 c.622C>T (p.Arg208X) variant results in a premature termination codon, predicted to cause a truncated or absent TPP1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 21/121276 control chromosomes at a frequency of 0.0001732, which does not exceed the estimated maximal expected allele frequency of a pathogenic TPP1 variant (0.002958). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state and is reported as one of the most common pathogenic variants in the gene. In vitro functional studies reveal no translational product could be detected for the R208X mutant and enzyme activity was shown to be <10% and not significantly different from negative controls (Steinfeld_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a common disease causing variant and has been classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Aug 17, 2012	- -

TPP1-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 11, 2024	PVS1, PM3_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 18, 2023	The TPP1 c.622C>T variant is predicted to result in premature protein termination (p.Arg208*). This is one of the most commonly reported TPP1 variants in individuals with neuronal ceroid lipofuscinosis; it has been observed in the homozygous state or with a second TPP1 variant in affected individuals (for example, see Sleat et al. 1997. PubMed ID: 9295267; Barisić et al. 2003. PubMed ID: 12950156; Miller et al. 2013. PubMed ID: 23539563; Geraets et al. 2017. PubMed ID: 28464005). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in TPP1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2021

The c.622C>T (p.R208*) alteration, located in exon 6 (coding exon 6) of the TPP1 gene, consists of a C to T substitution at nucleotide position 622. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 208. 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. This mutation is one of the most common TPP1 mutations and has been detected in both the homozygous and compound heterozygous states in various individuals with neuronal ceroid lipofuscinosis (Sleat, 1997; Barisi, 2003; Miller, 2013; Helbig, 2016). This mutation has been shown to significantly impact both TPP1 fold regulation and enzyme activity (Miller, 2013). Based on the available evidence, this alteration is classified as pathogenic. -

Abnormality of the nervous system Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A
Vest4		0.88
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 6

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

Publications

LitVar

Other links and lift over

dbSNP: rs119455955; hg19: chr11-6638271; COSMIC: COSV54993427; COSMIC: COSV54993427;