NM_000391.4(TPP1):c.509-1G>A AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jun 15, 2024
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:: RCV000189764.14

Allele description [Variation Report for NM_000391.4(TPP1):c.509-1G>A]

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

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>A

HGVS:

NC_000011.10:g.6617154C>T
NG_008653.1:g.7308G>A
NM_000391.4:c.509-1G>AMANE SELECT
LRG_830t1:c.509-1G>A
LRG_830:g.7308G>A
NC_000011.9:g.6638385C>T
NM_000391.3:c.509-1G>A

Links:

dbSNP: rs56144125

NCBI 1000 Genomes Browser:

rs56144125

Molecular consequence:

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

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
SCV000243412	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 15, 2024)	germline	clinical testing	Citation Link,
SCV000801148	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Pathogenic (Oct 22, 2015)	unknown	clinical testing
SCV000949765	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10330339, 22832778, 10356316, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000243412

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 15, 2024)

germline

clinical testing

Citation Link,

SCV000801148

Mayo Clinic Laboratories, Mayo Clinic

no assertion criteria provided

Pathogenic
(Oct 22, 2015)

unknown

clinical testing

SCV000949765

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 24, 2024)

germline

clinical testing

PubMed (4)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	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

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

Late infantile neuronal ceroid lipofuscinosis: mutations in the CLN2 gene and clinical course in Spanish patients.

Pérez-Poyato MS, Marfa MP, Abizanda IF, Rodriguez-Revenga L, Sánchez VC, González MJ, Puñal JE, Pérez AV, González MM, Bermejo AM, Hernández EM, Rosell MJ, Gort L, Milá M.

J Child Neurol. 2013 Apr;28(4):470-8. doi: 10.1177/0883073812448459. Epub 2012 Jul 25.

PubMed [citation]

PMID:: 22832778

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000243412.15

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

Description

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26143525, 22344438, 10356316, 10330339, 21940688, 31440721, 21990111)

#	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

From Mayo Clinic Laboratories, Mayo Clinic, SCV000801148.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000949765.6

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

Description

This sequence change affects an acceptor splice site in intron 5 of the TPP1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs56144125, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 10330339, 10356316, 22832778). This variant is also known as c.3556G>A and T523-1G>A. ClinVar contains an entry for this variant (Variation ID: 207574). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 10356316). The resulting mRNA is expected to undergo nonsense-mediated decay. 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: Sep 29, 2024

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