NM_000391.4(TPP1):c.1016G>A (p.Arg339Gln) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Pathogenic(1);Uncertain significance(1) (Last evaluated: Oct 15, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000180153.5

Allele description [Variation Report for NM_000391.4(TPP1):c.1016G>A (p.Arg339Gln)]

NM_000391.4(TPP1):c.1016G>A (p.Arg339Gln)

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.1016G>A (p.Arg339Gln)
HGVS:
  • NC_000011.10:g.6616374C>T
  • NG_008653.1:g.8088G>A
  • NM_000391.4:c.1016G>AMANE SELECT
  • NP_000382.3:p.Arg339Gln
  • LRG_830t1:c.1016G>A
  • LRG_830:g.8088G>A
  • LRG_830p1:p.Arg339Gln
  • NC_000011.9:g.6637605C>T
  • NM_000391.3:c.1016G>A
  • O14773:p.Arg339Gln
Protein change:
R339Q
Links:
UniProtKB: O14773#VAR_066886; dbSNP: rs765380155
NCBI 1000 Genomes Browser:
rs765380155
Molecular consequence:
  • NM_000391.4:c.1016G>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
variation affecting protein [Variation Ontology: 0002]
Observations:
2

Condition(s)

Identifiers:
MedGen: CN517202

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000232543EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Uncertain significance
(Sep 17, 2014)
germlineclinical testing

Citation Link,

SCV000827926Invitaecriteria provided, single submitter
Pathogenic
(Jul 30, 2020)
germlineclinical testing

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

SCV001778011GeneDxcriteria provided, single submitter
Likely pathogenic
(Oct 15, 2020)
germlineclinical testing

Citation Link,

SCV001808621Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensusno assertion criteria providedLikely pathogenicgermlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown2not providednot providednot providednot providedclinical testing

Citations

PubMed

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

Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America.

Kohan R, Carabelos MN, Xin W, Sims K, Guelbert N, Cismondi IA, Pons P, Alonso GI, Troncoso M, Witting S, Pearce DA, Dodelson de Kremer R, Oller-Ramírez AM, Noher de Halac I.

Gene. 2013 Mar 1;516(1):114-21. doi: 10.1016/j.gene.2012.12.058. Epub 2012 Dec 22.

PubMed [citation]
PMID:
23266810
PMCID:
PMC3855401
See all PubMed Citations (4)

Details of each submission

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000232543.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not providednot providednot provided

From Invitae, SCV000827926.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine with glutamine at codon 339 of the TPP1 protein (p.Arg339Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs765380155, ExAC 0.001%). This variant has been reported as homozygous or in combination with another TPP1 variant in individuals with low TPP1 enzyme activities, findings that are highly specific for CLN2 (PMID: 22832778, 23266810). ClinVar contains an entry for this variant (Variation ID: 198725). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Pro339Trp) has been determined to be pathogenic (PMID: 24091540, Invitae). This suggests that the arginine residue is critical for TPP1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV001778011.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32298681, 30541466, 29056246, 23266810, 21990111, 19038966)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001808621.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

Support Center