NM_000391.4(TPP1):c.381-2A>G AND Neuronal ceroid lipofuscinosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 1, 2017
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:: RCV000589489.1

Allele description [Variation Report for NM_000391.4(TPP1):c.381-2A>G]

NM_000391.4(TPP1):c.381-2A>G

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.381-2A>G

HGVS:

NC_000011.10:g.6617430T>C
NG_008653.1:g.7032A>G
NM_000391.4:c.381-2A>GMANE SELECT
LRG_830t1:c.381-2A>G
LRG_830:g.7032A>G
NC_000011.9:g.6638661T>C
NM_000391.3:c.381-2A>G

Links:

dbSNP: rs1554902052

NCBI 1000 Genomes Browser:

rs1554902052

Molecular consequence:

NM_000391.4:c.381-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000696664	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 1, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11339651, 25525159 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000696664

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(May 1, 2017)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

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

Heterogeneity of late-infantile neuronal ceroid lipofuscinosis.

Zhong N, Moroziewicz DN, Ju W, Jurkiewicz A, Johnston L, Wisniewski KE, Brown WT.

Genet Med. 2000 Nov-Dec;2(6):312-8.

PubMed [citation]

PMID:: 11339651

RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.

Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ.

Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.

PubMed [citation]

PMID:: 25525159
PMCID:: PMC4362528

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696664.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: The TPP1 c.381-2A>G (IVS4-2A>G) variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict significant impact on normal splicing-loss of canonical splicing acceptor site. ESEfinder predicts changes of binding motifs for splicing enhancers. Consistently, Xiong_2015 used computational modeling and predicted variant to induce large splicing changes. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121164 control chromosomes. The variant of interest has reported in an affected individual with LINCL as compound heterozygote. Taken together, due to lack of clinical and functional evidence, this variant is classified as likely 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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