NM_000391.4(TPP1):c.827A>T (p.Asp276Val) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 3, 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:: RCV000189773.11

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]

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
SCV000243421	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 12, 2023)	germline	clinical testing	Citation Link,
SCV000951555	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 3, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19793312, 22832778, 23266810, 25976102, 28492532
SCV002022407	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000243421

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 12, 2023)

germline

clinical testing

Citation Link,

SCV000951555

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 3, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002022407

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 23, 2022)

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	germline	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

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

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 (6)

Details of each submission

From GeneDx, SCV000243421.11

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 32488064, 33084218, 28792770, 25976102, 29655203, 19793312, 31440721, 23266810, 33377563, 31283065)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000951555.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 276 of the TPP1 protein (p.Asp276Val). This variant is present in population databases (rs763162812, gnomAD 0.01%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis type 2 (PMID: 19793312, 22832778, 23266810, 25976102). 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: 207581). 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%. 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

From Revvity Omics, Revvity, SCV002022407.3

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

Last Updated: Nov 3, 2024

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