Submissions for variant NM_000391.4(TPP1):c.622C>T (p.Arg208Ter)

gnomAD frequency: 0.00025  dbSNP: rs119455955

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189769	SCV000243417	pathogenic	not provided	2021-04-22	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV000210605	SCV000262903	pathogenic	Inborn genetic diseases	2016-11-30	criteria provided, single submitter	clinical testing	The p.R208* pathogenic mutation (also known as c.622C>T), located in coding exon 6 of the TPP1 gene, results from a C to T substitution at nucleotide position 622. This changes the amino acid from an arginine to a stop codon within coding exon 6. 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 (NCL) (Sleat DE et al. Science, 1997 Sep;277:1802-5; Barisi N et al. Croat. Med. J., 2003 Aug;44:489-93; Helbig KL et al. Genet. Med., 2016 Sep;18:898-905; Miller JN et al. Hum. Mol. Genet., 2013 Jul;22:2723-34). In addition, this mutation has been shown to significantly impact both TPP1 fold regulation and enzyme activity (Miller JN et al. Hum. Mol. Genet., 2013 Jul;22:2723-34). 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.
Invitae	RCV000189769	SCV000284808	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	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.
Genetic Services Laboratory, University of Chicago	RCV000002762	SCV000597531	pathogenic	Neuronal ceroid lipofuscinosis 2	2016-03-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763267	SCV000611330	pathogenic	Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7	2022-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000189769	SCV000615830	pathogenic	not provided	2017-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000230952	SCV000696667	pathogenic	Neuronal ceroid lipofuscinosis	2016-08-11	criteria provided, single submitter	clinical testing	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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000002762	SCV000744909	pathogenic	Neuronal ceroid lipofuscinosis 2	2017-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763267	SCV000893910	pathogenic	Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000002762	SCV000915543	pathogenic	Neuronal ceroid lipofuscinosis 2	2018-08-14	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000002762	SCV001163320	pathogenic	Neuronal ceroid lipofuscinosis 2		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000002762	SCV001194158	pathogenic	Neuronal ceroid lipofuscinosis 2	2019-10-18	criteria provided, single submitter	clinical testing	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
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000002762	SCV001366393	pathogenic	Neuronal ceroid lipofuscinosis 2	2019-01-09	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Blueprint Genetics	RCV000002762	SCV001426166	pathogenic	Neuronal ceroid lipofuscinosis 2	2018-09-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000189769	SCV001748276	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TPP1: PM3:Very Strong, PVS1, PM2, PS3:Supporting
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813939	SCV001755651	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000189769	SCV002022403	pathogenic	not provided	2022-11-18	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000002762	SCV002580602	pathogenic	Neuronal ceroid lipofuscinosis 2	2022-01-18	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000002762	SCV004042679	pathogenic	Neuronal ceroid lipofuscinosis 2		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398423	SCV004121302	pathogenic	TPP1-related condition	2023-12-18	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000189769	SCV004227217	pathogenic	not provided	2023-03-24	criteria provided, single submitter	clinical testing	PM2, PS3, PS4_moderate, PVS1
OMIM	RCV000002762	SCV000022920	pathogenic	Neuronal ceroid lipofuscinosis 2	1997-09-19	no assertion criteria provided	literature only
GeneReviews	RCV000002762	SCV000086785	not provided	Neuronal ceroid lipofuscinosis 2		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000002762	SCV000733089	pathogenic	Neuronal ceroid lipofuscinosis 2		no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000230952	SCV000804935	pathogenic	Neuronal ceroid lipofuscinosis	2012-08-17	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000002762	SCV001459947	pathogenic	Neuronal ceroid lipofuscinosis 2	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000189769	SCV001798173	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000189769	SCV001959365	pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000002762	SCV004101088	pathogenic	Neuronal ceroid lipofuscinosis 2	2023-11-02	no assertion criteria provided	clinical testing