NM_000391.4(TPP1):c.509-1G>C AND Inborn genetic diseases

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 23, 2018
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:: RCV000210689.5

Allele description

NM_000391.4(TPP1):c.509-1G>C

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.509-1G>C

HGVS:

NC_000011.10:g.6617154C>G
NG_008653.1:g.7308G>C
NM_000391.4:c.509-1G>CMANE SELECT
LRG_830t1:c.509-1G>C
LRG_830:g.7308G>C
NC_000011.9:g.6638385C>G
NM_000391.3:c.509-1G>C
NM_000391.3:c.509-1G>C(IVS5-1G>C)

Nucleotide change:

IVS5AS, G-C, -1

Links:

Genetic Testing Registry (GTR): GTR000330881; OMIM: 607998.0004; dbSNP: rs56144125

NCBI 1000 Genomes Browser:

rs56144125

Molecular consequence:

NM_000391.4:c.509-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000262910	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Aug 23, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10330339, 23539563, 26224725, 28335910, 9295267, 9788728 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000262910

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Aug 23, 2018)

germline

clinical testing

PubMed (6)
[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	1	not provided	not provided	1	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

The role of nonsense-mediated decay in neuronal ceroid lipofuscinosis.

Miller JN, Chan CH, Pearce DA.

Hum Mol Genet. 2013 Jul 1;22(13):2723-34. doi: 10.1093/hmg/ddt120. Epub 2013 Mar 28.

PubMed [citation]

PMID:: 23539563
PMCID:: PMC4439521

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000262910.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

The c.509-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 6 of the TPP1 gene. This mutation has been well described as one of the most common mutations causing late infantile neuronal ceroid lipofuscinosis (CLN2), having been reported in the homozygous and compound heterozygous state in numerous affected individuals across various ethnic backgrounds (Williams RE et al. Pediatr. Neurol., 2017 Apr;69:102-112; Sleat DE et al. Am. J. Hum. Genet. 1999;64(6):1511-23, Zhong N et al. Clin. Genet. 1998;54(3):234-8). This mutation has also been reported in individuals with autosomal recessive spinocereballar ataxia (SCAR7) (Dy ME, et al. Neurology 2015;85(14):1259-61). In one RNA study, RT-PCR analysis revealed retention of intron 5, resulting in a frameshift and premature protein truncation. Furthermore, residual enzyme activity in probands was reduced to 9% in CLN2 and 15% in SCAR7 compared to unaffected family members (Miller JN et al. Hum. Mol. Genet. 2013;22(13):2723-34). Based on the available evidence, c.509-1G>C is classified as a pathogenic mutation.

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

Last Updated: Apr 20, 2024

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