NM_001042432.2(CLN3):c.883G>T (p.Glu295Ter) AND Neuronal ceroid lipofuscinosis

Clinical significance:Pathogenic (Last evaluated: Mar 11, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001055217.3

Allele description [Variation Report for NM_001042432.2(CLN3):c.883G>T (p.Glu295Ter)]

NM_001042432.2(CLN3):c.883G>T (p.Glu295Ter)

Gene:
CLN3:CLN3 lysosomal/endosomal transmembrane protein, battenin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16p12.1
Genomic location:
Preferred name:
NM_001042432.2(CLN3):c.883G>T (p.Glu295Ter)
HGVS:
  • NC_000016.10:g.28482500C>A
  • NG_008654.2:g.14803G>T
  • NM_000086.2:c.883G>T
  • NM_001042432.2:c.883G>TMANE SELECT
  • NM_001286104.2:c.811G>T
  • NM_001286105.2:c.583G>T
  • NM_001286109.2:c.649G>T
  • NM_001286110.2:c.721G>T
  • NP_000077.1:p.Glu295Ter
  • NP_001035897.1:p.Glu295Ter
  • NP_001035897.1:p.Glu295Ter
  • NP_001273033.1:p.Glu271Ter
  • NP_001273034.1:p.Glu195Ter
  • NP_001273038.1:p.Glu217Ter
  • NP_001273039.1:p.Glu241Ter
  • LRG_689t1:c.883G>T
  • LRG_689t2:c.883G>T
  • LRG_689:g.14803G>T
  • LRG_689p1:p.Glu295Ter
  • LRG_689p2:p.Glu295Ter
  • NC_000016.9:g.28493821C>A
  • NM_000086.2:c.883G>T
  • NM_001042432.1:c.883G>T
Protein change:
E195*
Links:
dbSNP: rs121434286
NCBI 1000 Genomes Browser:
rs121434286
Molecular consequence:
  • NM_000086.2:c.883G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001042432.2:c.883G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001286104.2:c.811G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001286105.2:c.583G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001286109.2:c.649G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001286110.2:c.721G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Neuronal ceroid lipofuscinosis
Synonyms:
Ceroid storage disease; Lipofuscin storage disease
Identifiers:
MONDO: MONDO:0016295; MedGen: C0027877; Orphanet: 79263; OMIM: PS256730

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001219595Invitaecriteria provided, single submitter
Pathogenic
(Feb 18, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001519540Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Mar 11, 2021)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Spectrum of mutations in the Batten disease gene, CLN3.

Munroe PB, Mitchison HM, O'Rawe AM, Anderson JW, Boustany RM, Lerner TJ, Taschner PE, de Vos N, Breuning MH, Gardiner RM, Mole SE.

Am J Hum Genet. 1997 Aug;61(2):310-6.

PubMed [citation]
PMID:
9311735
PMCID:
PMC1715900

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV001219595.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Glu295*) in the CLN3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another CLN3 variant in an individual affected with retinal degeneration (PMID: 28542676). ClinVar contains an entry for this variant (Variation ID: 56290). Loss-of-function variants in CLN3 are known to be pathogenic (PMID: 9311735, 28542676). For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001519540.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: CLN3 c.883G>T (p.Glu295X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251470 control chromosomes (gnomAD). c.883G>T has been reported in the literature in individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease) and isolated retinal degeneration (Zhong_2000, Kousi_2012, Bell_2011, Ku_2017, Turriff_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Dec 4, 2021

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