NM_001042432.2(CLN3):c.1000C>T (p.Arg334Cys) AND Neuronal ceroid lipofuscinosis

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jul 9, 2020)

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:
RCV000588369.4

Allele description [Variation Report for NM_001042432.2(CLN3):c.1000C>T (p.Arg334Cys)]

NM_001042432.2(CLN3):c.1000C>T (p.Arg334Cys)

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.1000C>T (p.Arg334Cys)
HGVS:
  • NC_000016.10:g.28482161G>A
  • NG_008654.2:g.15142C>T
  • NM_000086.2:c.1000C>T
  • NM_001042432.1:c.1000C>T
  • NM_001042432.2:c.1000C>TMANE SELECT
  • NM_001286104.2:c.928C>T
  • NM_001286105.2:c.700C>T
  • NM_001286109.2:c.766C>T
  • NM_001286110.2:c.838C>T
  • NP_000077.1:p.Arg334Cys
  • NP_001035897.1:p.Arg334Cys
  • NP_001035897.1:p.Arg334Cys
  • NP_001273033.1:p.Arg310Cys
  • NP_001273034.1:p.Arg234Cys
  • NP_001273038.1:p.Arg256Cys
  • NP_001273039.1:p.Arg280Cys
  • LRG_689t1:c.1000C>T
  • LRG_689t2:c.1000C>T
  • LRG_689:g.15142C>T
  • LRG_689p1:p.Arg334Cys
  • LRG_689p2:p.Arg334Cys
  • NC_000016.9:g.28493482G>A
  • Q13286:p.Arg334Cys
Protein change:
R234C
Links:
UniProtKB: Q13286#VAR_005135; dbSNP: rs386833694
NCBI 1000 Genomes Browser:
rs386833694
Molecular consequence:
  • NM_000086.2:c.1000C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042432.1:c.1000C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042432.2:c.1000C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286104.2:c.928C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286105.2:c.700C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286109.2:c.766C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286110.2:c.838C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000697651Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Mar 21, 2019)
germlineclinical testing

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

Citation Link,

SCV001232832Invitaecriteria provided, single submitter
Pathogenic
(Jul 9, 2020)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

btn1, the Schizosaccharomyces pombe homologue of the human Batten disease gene CLN3, regulates vacuole homeostasis.

Gachet Y, Codlin S, Hyams JS, Mole SE.

J Cell Sci. 2005 Dec 1;118(Pt 23):5525-36. Epub 2005 Nov 15.

PubMed [citation]
PMID:
16291725

Batten disease: evaluation of CLN3 mutations on protein localization and function.

Haskell RE, Carr CJ, Pearce DA, Bennett MJ, Davidson BL.

Hum Mol Genet. 2000 Mar 22;9(5):735-44.

PubMed [citation]
PMID:
10749980
See all PubMed Citations (14)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697651.2

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

Description

Variant summary: CLN3 c.1000C>T (p.Arg334Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 275064 control chromosomes (gnomAD). c.1000C>T has been reported in the literature in individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease). These data indicate that the variant may be associated with disease. The c.1000C>T variant has been reported in the literature in several individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease), indicating that the variant may be associated with disease. Additionally, a variant affecting the same codon c.1001G>A (p.R334H) was also observed in 4 families with classical JNCL phenotype, indicating residue 334 is likely critical for normal function of the CLN3 protein. The variant is located in the third lumenal region on the predicted lumenal face of a putative amphipathic helix, and all proteins mutated in this region were defective in function observed by a functional study (Haines_2009), suggesting this region has a significant effect on the protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

From Invitae, SCV001232832.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This sequence change replaces arginine with cysteine at codon 334 of the CLN3 protein (p.Arg334Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs386833694, ExAC 0.01%). This variant has been observed in individuals with neuronal ceroid lipofuscinosis (PMID: 9311735, 25976102, 17475770, 21990111). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56243). This variant has been reported to affect CLN3 protein function (PMID: 19132115, 11589014, 10924275, 17475770). This variant disrupts the p.Arg334 amino acid residue in CLN3. Other variant(s) that disrupt this residue have been observed in individuals with CLN3-related conditions (PMID: 21990111, 21499717, 23539563, 9311735, 20187884), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 30, 2021

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