NM_000391.4(TPP1):c.605C>T (p.Pro202Leu) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 21, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001854254.3

Allele description [Variation Report for NM_000391.4(TPP1):c.605C>T (p.Pro202Leu)]

NM_000391.4(TPP1):c.605C>T (p.Pro202Leu)

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.605C>T (p.Pro202Leu)

HGVS:

NC_000011.10:g.6617057G>A
NG_008653.1:g.7405C>T
NM_000391.4:c.605C>TMANE SELECT
NP_000382.3:p.Pro202Leu
LRG_830t1:c.605C>T
LRG_830:g.7405C>T
LRG_830p1:p.Pro202Leu
NC_000011.9:g.6638288G>A
NM_000391.3:c.605C>T
O14773:p.Pro202Leu

Protein change:

P202L

Links:

UniProtKB: O14773#VAR_063640; UniProtKB/Swiss-Prot: VAR_063640; dbSNP: rs121908205

NCBI 1000 Genomes Browser:

rs121908205

Molecular consequence:

NM_000391.4:c.605C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002247008	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11589012, 20340139, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002247008

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 21, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

New mutations in the neuronal ceroid lipofuscinosis genes.

Mole SE, Zhong NA, Sarpong A, Logan WP, Hofmann S, Yi W, Franken PF, van Diggelen OP, Breuning MH, Moroziewicz D, Ju W, Salonen T, Holmberg V, Järvelä I, Taschner PE.

Eur J Paediatr Neurol. 2001;5 Suppl A:7-10. Review.

PubMed [citation]

PMID:: 11589012

Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I.

Walus M, Kida E, Golabek AA.

Hum Mutat. 2010 Jun;31(6):710-21. doi: 10.1002/humu.21251.

PubMed [citation]

PMID:: 20340139

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV002247008.3

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

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 202 of the TPP1 protein (p.Pro202Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 11589012; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 68747). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPP1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TPP1 function (PMID: 20340139). 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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