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NM_001042432.2(CLN3):c.1247A>G (p.Asp416Gly) AND Neuronal ceroid lipofuscinosis

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jun 27, 2023
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:
RCV003317069.1

Allele description [Variation Report for NM_001042432.2(CLN3):c.1247A>G (p.Asp416Gly)]

NM_001042432.2(CLN3):c.1247A>G (p.Asp416Gly)

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.1247A>G (p.Asp416Gly)
HGVS:
  • NC_000016.10:g.28477586T>C
  • NG_008654.2:g.19717A>G
  • NM_000086.2:c.1247A>G
  • NM_001042432.2:c.1247A>GMANE SELECT
  • NM_001286104.2:c.1175A>G
  • NM_001286105.2:c.947A>G
  • NM_001286109.2:c.1013A>G
  • NM_001286110.2:c.1085A>G
  • NP_000077.1:p.Asp416Gly
  • NP_001035897.1:p.Asp416Gly
  • NP_001035897.1:p.Asp416Gly
  • NP_001273033.1:p.Asp392Gly
  • NP_001273034.1:p.Asp316Gly
  • NP_001273038.1:p.Asp338Gly
  • NP_001273039.1:p.Asp362Gly
  • LRG_689t1:c.1247A>G
  • LRG_689t2:c.1247A>G
  • LRG_689:g.19717A>G
  • LRG_689p1:p.Asp416Gly
  • LRG_689p2:p.Asp416Gly
  • NC_000016.9:g.28488907T>C
  • NM_001042432.1:c.1247A>G
Protein change:
D316G
Links:
dbSNP: rs386833703
NCBI 1000 Genomes Browser:
rs386833703
Molecular consequence:
  • NM_000086.2:c.1247A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042432.2:c.1247A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286104.2:c.1175A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286105.2:c.947A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286109.2:c.1013A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286110.2:c.1085A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Neuronal ceroid lipofuscinosis
Synonyms:
Ceroid 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
SCV004020770Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Jun 27, 2023)
germlineclinical testing

PubMed (5)
[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

Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease).

Kwon JM, Adams H, Rothberg PG, Augustine EF, Marshall FJ, Deblieck EA, Vierhile A, Beck CA, Newhouse NJ, Cialone J, Levy E, Ramirez-Montealegre D, Dure LS, Rose KR, Mink JW.

Neurology. 2011 Nov 15;77(20):1801-7. doi: 10.1212/WNL.0b013e318237f649. Epub 2011 Oct 19.

PubMed [citation]
PMID:
22013180
PMCID:
PMC3233207

Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway.

Lojewski X, Staropoli JF, Biswas-Legrand S, Simas AM, Haliw L, Selig MK, Coppel SH, Goss KA, Petcherski A, Chandrachud U, Sheridan SD, Lucente D, Sims KB, Gusella JF, Sondhi D, Crystal RG, Reinhardt P, Sterneckert J, Schöler H, Haggarty SJ, Storch A, Hermann A, et al.

Hum Mol Genet. 2014 Apr 15;23(8):2005-22. doi: 10.1093/hmg/ddt596. Epub 2013 Nov 23.

PubMed [citation]
PMID:
24271013
PMCID:
PMC3959814
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020770.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: CLN3 c.1247A>G (p.Asp416Gly) results in a non-conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250758 control chromosomes (gnomAD). c.1247A>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease, Kwon_2011, Lojewski_2014, Sleat_2017), and they were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. Publications report experimental evidence evaluating an impact of the variant protein in iPSCs, finding reductions in TRPML1 activation, endolysosomal localization, and proteolysis, as well as expansion of the lysosomal compartment (Prat Castro_2022, Scotto Rosato_2022). The following publications have been ascertained in the context of this evaluation (PMID: 22013180, 24271013, 28792770, 36139381, 35929194). No submitters have cited 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

Last Updated: Jun 17, 2024