NM_000391.4(TPP1):c.616C>T (p.Arg206Cys) AND Neuronal ceroid lipofuscinosis 2

Germline classification:: Pathogenic (5 submissions)
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000002765.15

Allele description [Variation Report for NM_000391.4(TPP1):c.616C>T (p.Arg206Cys)]

NM_000391.4(TPP1):c.616C>T (p.Arg206Cys)

Gene:

TPP1:tripeptidyl peptidase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000391.4(TPP1):c.616C>T (p.Arg206Cys)

HGVS:

NC_000011.10:g.6617046G>A
NG_008653.1:g.7416C>T
NM_000391.4:c.616C>TMANE SELECT
NP_000382.3:p.Arg206Cys
LRG_830t1:c.616C>T
LRG_830:g.7416C>T
LRG_830p1:p.Arg206Cys
NC_000011.9:g.6638277G>A
NM_000391.3:c.616C>T
O14773:p.Arg206Cys

Protein change:

R206C; ARG206CYS

Links:

UniProtKB: O14773#VAR_009605; UniProtKB/Swiss-Prot: VAR_009605; OMIM: 607998.0006; dbSNP: rs28940573

NCBI 1000 Genomes Browser:

rs28940573

Molecular consequence:

NM_000391.4:c.616C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Unknown function

Observations:

Condition(s)

Name:: Neuronal ceroid lipofuscinosis 2
Synonyms:: JANSKY-BIELSCHOWSKY DISEASE NEURONAL CEROID LIPOFUSCINOSIS, LATE INFANTILE; TPP1-Related Neuronal Ceroid-Lipofuscinosis
Identifiers:: MONDO: MONDO:0008769; MedGen: C1876161; Orphanet: 168491; Orphanet: 228349; Orphanet: 79264; OMIM: 204500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022923	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2000)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000091197	UniProtKB/Swiss-Prot	no classification provided	not provided	not provided	not provided	PubMed (2) [See all records that cite these PMIDs] 10665500, 12698559
SCV002094863	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 10, 2020)	germline	clinical testing
SCV002754481	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005060865	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Prenatal testing for late infantile neuronal ceroid lipofuscinosis.

Berry-Kravis E, Sleat DE, Sohar I, Meyer P, Donnelly R, Lobel P.

Ann Neurol. 2000 Feb;47(2):254-7.

PubMed [citation]

PMID:: 10665500

[Tripeptidyl peptidase 1 deficiency in neuronal ceroid lipofuscinosis. A novel mutation].

Bukina AM, Tsvetkova IV, Semiachkina AN, Il'ina ES.

Vopr Med Khim. 2002 Nov-Dec;48(6):594-8. Russian.

PubMed [citation]

PMID:: 12698559

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000022923.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a family with first-cousin parents, Berry-Kravis et al. (2000) demonstrated a 3664C-T transition in the CLN2 gene, resulting in an arg206-to-cys mutation (R206C), as the cause of late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500) and used the mutation successfully for prenatal diagnosis, demonstrating that the fetus at risk was homozygous for the wildtype alleles. The homozygous proband had developed seizures at age 3 years and was unable to ambulate independently by age 5. Electron microscopy performed on a skin biopsy demonstrated curvilinear bodies typical of CLN2.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From UniProtKB/Swiss-Prot, SCV000091197.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not provided	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002094863.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV002754481.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (1)

Description

A Homozygous missense variation in exon 6 of the TPP1 gene that results in the amino acid substitution of Cysteine for Arginine at codon 206 was detected. The observed variant c.616C>T (p.Arg206Cys) has not been reported in the 1000 genomes and has MAF of 0.001% in gnomAD databases. The in silico prediction of the variant are possibly damaging by DANN, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV005060865.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The observed missense c.616C>T(p.Arg206Cys) variant in TPP1 gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with Neuronal ceroid lipofuscinoses type II (NCL2) / Batten disease (Sheth et al., 2018). Experimental studies have shown that this missense change affects TPP1 function (Walus et al., 2010). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Arg at position 206 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg206Cys in TPP1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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