The Q352X nonsense variant in the CLN3 gene has been reported previously in association with juvenile neuronal ceroid lipofucinosis (Munroe et al., 1997, Miller et al., 2013). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q352X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this nonsense variant is considered to be a pathogenic variant.
ClinVar Genomic variation as it relates to human health
NM_001042432.2(CLN3):c.1054C>T (p.Gln352Ter)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
6 out of 10 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
10
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001042432.2(CLN3):c.1054C>T (p.Gln352Ter)
Variation ID: 56246 Accession: VCV000056246.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p12.1 16: 28482107 (GRCh38) [ NCBI UCSC ] 16: 28493428 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 24, 2013 Jun 29, 2025 Jan 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001042432.2:c.1054C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035897.1:p.Gln352Ter nonsense NM_000086.2:c.1054C>T NP_000077.1:p.Gln352Ter nonsense NM_001286104.2:c.982C>T NP_001273033.1:p.Gln328Ter nonsense NM_001286105.2:c.754C>T NP_001273034.1:p.Gln252Ter nonsense NM_001286109.2:c.820C>T NP_001273038.1:p.Gln274Ter nonsense NM_001286110.2:c.892C>T NP_001273039.1:p.Gln298Ter nonsense NC_000016.10:g.28482107G>A NC_000016.9:g.28493428G>A NG_008654.2:g.15196C>T LRG_689:g.15196C>T LRG_689t1:c.1054C>T LRG_689p1:p.Gln352Ter LRG_689t2:c.1054C>T LRG_689p2:p.Gln352Ter - Protein change
- Q352*, Q252*, Q274*, Q328*, Q298*
- Other names
- -
- Canonical SPDI
- NC_000016.10:28482106:G:A
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CLN3 | Gene associated with autosomal recessive phenotype | Not yet evaluated |
GRCh38 GRCh37 |
1227 | 1312 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 25, 2024 | RCV000049658.8 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Oct 10, 2017 | RCV000579238.4 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2023 | RCV001804785.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2023 | RCV004814987.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 10, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000680509.1
First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018 |
Comment:
show
The Q352X nonsense variant in the CLN3 gene has been reported previously in association with juvenile neuronal ceroid lipofucinosis (Munroe et al., 1997, Miller et al., 2013). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q352X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this nonsense variant is considered to be a pathogenic variant. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Aug 10, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis 3 |
Genome-Nilou Lab
Accession: SCV001977441.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
|
|
|
Pathogenic
(Dec 17, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002051191.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
show
Variant summary: CLN3 c.1054C>T (p.Gln352X) 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. The variant allele was found at a frequency of 8.1e-06 in 245602 control chromosomes (gnomAD). c.1054C>T has been reported in the literature in multiple individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease) (examples: Munroe_1997, Miller_2013, Kousi_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence, and demonstrated that the CLN3 mRNA level was decreased in LCLs derived from a homozygous patient, presumably due to nonsense mediated decay (Miller_2013). Three ClinVar submitter have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jan 25, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis 3 |
Baylor Genetics
Accession: SCV004214307.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jan 01, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Retinal dystrophy |
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV005070398.1
First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(May 01, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002241056.4
First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025 |
Comment:
show
This sequence change creates a premature translational stop signal (p.Gln352*) in the CLN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN3 are known to be pathogenic (PMID: 9311735, 28542676). This variant is present in population databases (rs386833697, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with CLN3-related conditions (PMID: 9311735, 23539563). ClinVar contains an entry for this variant (Variation ID: 56246). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Mar 06, 2018)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Neuronal ceroid lipofuscinosis 3 |
Counsyl
Accession: SCV000798303.3
First in ClinVar: Jul 24, 2013 Last updated: Jun 29, 2025 |
Comment:
show
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922197.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973063.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Juvenile neuronal ceroid lipofuscinosis |
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082065.2
First in ClinVar: Jul 24, 2013 Last updated: Jun 08, 2025
Comment:
FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
|
Observation: 1
Collection method: not provided
Allele origin: unknown
Affected status: not provided
Observation 1
Collection method: not provided
Allele origin: unknown
Affected status: not provided
|
|
Comment:
Comment:
Variant summary: CLN3 c.1054C>T (p.Gln352X) 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. The variant allele was found at a frequency of 8.1e-06 in 245602 control chromosomes (gnomAD). c.1054C>T has been reported in the literature in multiple individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease) (examples: Munroe_1997, Miller_2013, Kousi_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence, and demonstrated that the CLN3 mRNA level was decreased in LCLs derived from a homozygous patient, presumably due to nonsense mediated decay (Miller_2013). Three ClinVar submitter have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Gln352*) in the CLN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN3 are known to be pathogenic (PMID: 9311735, 28542676). This variant is present in population databases (rs386833697, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with CLN3-related conditions (PMID: 9311735, 23539563). ClinVar contains an entry for this variant (Variation ID: 56246). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Comment:
Converted during submission from probable-pathogenic to Likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration. | Ku CA | JAMA ophthalmology | 2017 | PMID: 28542676 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| The role of nonsense-mediated decay in neuronal ceroid lipofuscinosis. | Miller JN | Human molecular genetics | 2013 | PMID: 23539563 |
| Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. | Kousi M | Human mutation | 2012 | PMID: 21990111 |
| Spectrum of mutations in the Batten disease gene, CLN3. | Munroe PB | American journal of human genetics | 1997 | PMID: 9311735 |
Text-mined citations for rs386833697 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jun 29, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.