NM_000391.4(TPP1):c.1424C>T (p.Ser475Leu) AND Neuronal ceroid lipofuscinosis

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 7, 2022
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:: RCV002307388.1

Allele description [Variation Report for NM_000391.4(TPP1):c.1424C>T (p.Ser475Leu)]

NM_000391.4(TPP1):c.1424C>T (p.Ser475Leu)

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.1424C>T (p.Ser475Leu)

Other names:

5541C>T

HGVS:

NC_000011.10:g.6615172G>A
NG_008653.1:g.9290C>T
NM_000391.4:c.1424C>TMANE SELECT
NP_000382.3:p.Ser475Leu
LRG_830t1:c.1424C>T
LRG_830:g.9290C>T
LRG_830p1:p.Ser475Leu
NC_000011.9:g.6636403G>A
NM_000391.3:c.1424C>T
O14773:p.Ser475Leu

Protein change:

S475L

Links:

UniProtKB: O14773#VAR_009612; UniProtKB/Swiss-Prot: VAR_009612; dbSNP: rs121908202

NCBI 1000 Genomes Browser:

rs121908202

Molecular consequence:

NM_000391.4:c.1424C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neuronal ceroid lipofuscinosis
Synonyms:: Ceroid storage disease
Identifiers:: MONDO: MONDO:0016295; MedGen: C0027877; Orphanet: 79263; OMIM: PS256730

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002600335	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 7, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10330339, 20340139, 31139143, 31489614 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002600335

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 7, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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

Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder.

Sleat DE, Gin RM, Sohar I, Wisniewski K, Sklower-Brooks S, Pullarkat RK, Palmer DN, Lerner TJ, Boustany RM, Uldall P, Siakotos AN, Donnelly RJ, Lobel P.

Am J Hum Genet. 1999 Jun;64(6):1511-23. Erratum in: Am J Hum Genet. 2004 Dec;75(6):1158.

PubMed [citation]

PMID:: 10330339
PMCID:: PMC1377895

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 (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600335.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: TPP1 c.1424C>T (p.Ser475Leu) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 2.4e-05 in 251484 control chromosomes (gnomAD). c.1424C>T has been reported in the literature as a biallelic genotype in individuals affected with Neuronal Ceroid-Lipofuscinosis (e.g. Sleat_1999, Dozieres-Puyravel_2020) and refractory epilepsy with intellectual disability (e.g. Long_2019). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating the variant in Chinese Hamster Ovary cells showed that the variant had no detectable enzymatic activity (0% of wild-type) despite normal translation, post translational processing, and trafficking (Walus_2010). Five ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was 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: Mar 16, 2024

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