NM_000391.4(TPP1):c.827A>T (p.Asp276Val) AND Neuronal ceroid lipofuscinosis 2

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: May 20, 2023
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:: RCV000666770.5

Allele description [Variation Report for NM_000391.4(TPP1):c.827A>T (p.Asp276Val)]

NM_000391.4(TPP1):c.827A>T (p.Asp276Val)

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.827A>T (p.Asp276Val)

Other names:

p.D276V:GAT>GTT

HGVS:

NC_000011.10:g.6616720T>A
NG_008653.1:g.7742A>T
NM_000391.4:c.827A>TMANE SELECT
NP_000382.3:p.Asp276Val
LRG_830t1:c.827A>T
LRG_830:g.7742A>T
LRG_830p1:p.Asp276Val
NC_000011.9:g.6637951T>A
NM_000391.3:c.827A>T

Protein change:

D276V

Links:

dbSNP: rs763162812

NCBI 1000 Genomes Browser:

rs763162812

Molecular consequence:

NM_000391.4:c.827A>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000791120	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (May 2, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001146849	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 20, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25741868, 19793312, 23266810
SCV001455835	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV005382371	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 20, 2023)	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Citations

PubMed

An integrated strategy for the diagnosis of neuronal ceroid lipofuscinosis types 1 (CLN1) and 2 (CLN2) in eleven Latin American patients.

Kohan R, Cismondi IA, Kremer RD, Muller VJ, Guelbert N, Anzolini VT, Fietz MJ, Ramírez AM, Halac IN.

Clin Genet. 2009 Oct;76(4):372-82. doi: 10.1111/j.1399-0004.2009.01214.x.

PubMed [citation]

PMID:: 19793312

Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America.

Kohan R, Carabelos MN, Xin W, Sims K, Guelbert N, Cismondi IA, Pons P, Alonso GI, Troncoso M, Witting S, Pearce DA, Dodelson de Kremer R, Oller-Ramírez AM, Noher de Halac I.

Gene. 2013 Mar 1;516(1):114-21. doi: 10.1016/j.gene.2012.12.058. Epub 2012 Dec 22.

PubMed [citation]

PMID:: 23266810
PMCID:: PMC3855401

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000791120.1

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

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

From Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan, SCV001146849.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (3)

#	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 Natera, Inc., SCV001455835.1

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV005382371.1

#	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.827A>T(p.Asp276Val) variant in TPP1 gene has been reported previously in multiple individuals affected with neuronal ceroid lipofuscinosis type 2 (Kohan R, et al., 2015; Kohan R, et al., 2013; Kohan R, et al., 2009). Experimental studies indicate that this variant impacts the catalytic machinery of TPP1 gene (Walus M, et al., 2005). The p.Asp276Val variant has been reported with allele frequency of 0.002% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 276 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. 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: Nov 3, 2024

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