Variant summary: CLN6 c.150C>G (p.Tyr50X) 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 associated with Neuronal Ceroid Lipofuscinosis (NCL) in HGMD. The variant allele was found at a frequency of 8e-06 in 251404 control chromosomes. c.150C>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (DiFruscio_2015), and specifically in Kufs disease, a subtype of NCL (Arsov_2011, Talbot_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_017882.3(CLN6):c.150C>G (p.Tyr50Ter)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
4 out of 6 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.
6
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017882.3(CLN6):c.150C>G (p.Tyr50Ter)
Variation ID: 68094 Accession: VCV000068094.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q23 15: 68218584 (GRCh38) [ NCBI UCSC ] 15: 68510922 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 22, 2013 May 25, 2025 Dec 17, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_017882.3:c.150C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060352.1:p.Tyr50Ter nonsense NC_000015.10:g.68218584G>C NC_000015.9:g.68510922G>C NG_008764.2:g.43628C>G LRG_832:g.43628C>G LRG_832t1:c.150C>G LRG_832p1:p.Tyr50Ter - Protein change
- Y50*
- Other names
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Tyyr50X
- Canonical SPDI
- NC_000015.10:68218583:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- 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. |
|||
| CLN6 | - | - |
GRCh38 GRCh37 |
799 | 815 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 15, 2024 | RCV000058908.14 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 17, 2024 | RCV000702360.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2017 | RCV000668229.1 |
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. |
More information
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Feb 02, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844709.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: CLN6 c.150C>G (p.Tyr50X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: CLN6 c.150C>G (p.Tyr50X) 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 associated with Neuronal Ceroid Lipofuscinosis (NCL) in HGMD. The variant allele was found at a frequency of 8e-06 in 251404 control chromosomes. c.150C>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (DiFruscio_2015), and specifically in Kufs disease, a subtype of NCL (Arsov_2011, Talbot_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
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Pathogenic
(Nov 15, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568366.5
First in ClinVar: Oct 22, 2013 Last updated: Nov 24, 2024 |
Comment:
Reported previously in a patient with a clinical diagnosis of Kufs disease who was also heterozygous for two missense substitutions in the CLN6 gene, although … (more)
Reported previously in a patient with a clinical diagnosis of Kufs disease who was also heterozygous for two missense substitutions in the CLN6 gene, although no further clinical details were provided and parental testing was not performed to determine the phase of the three variants (PMID: 21549341); Reported previously as a pathogenic variant in a cohort of patients referred for epilepsy genetic testing; however, no specific clinical information was provided (PMID: 31440721); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 31440721, 26075876, 33024953, 21549341) (less)
|
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Pathogenic
(Dec 17, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000831212.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 25, 2025 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr50*) in the CLN6 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr50*) in the CLN6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN6 are known to be pathogenic (PMID: 19135028). This variant is present in population databases (rs154774640, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21549341, 26075876). ClinVar contains an entry for this variant (Variation ID: 68094). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Jan 01, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004703339.12
First in ClinVar: Mar 10, 2024 Last updated: May 25, 2025 |
Comment:
CLN6: PVS1, PM2, PM3
Number of individuals with the variant: 1
|
|
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Likely pathogenic
(Jul 14, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Ceroid lipofuscinosis, neuronal, 6A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000792797.2
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
germline
|
SNPedia
Accession: SCV000090429.1
First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013
Comment:
Kufs Type A disease
|
|
|
Comment:
Comment:
Reported previously in a patient with a clinical diagnosis of Kufs disease who was also heterozygous for two missense substitutions in the CLN6 gene, although no further clinical details were provided and parental testing was not performed to determine the phase of the three variants (PMID: 21549341); Reported previously as a pathogenic variant in a cohort of patients referred for epilepsy genetic testing; however, no specific clinical information was provided (PMID: 31440721); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 31440721, 26075876, 33024953, 21549341)
Comment:
This sequence change creates a premature translational stop signal (p.Tyr50*) in the CLN6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN6 are known to be pathogenic (PMID: 19135028). This variant is present in population databases (rs154774640, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21549341, 26075876). ClinVar contains an entry for this variant (Variation ID: 68094). For these reasons, this variant has been classified as Pathogenic.
Comment:
CLN6: PVS1, PM2, PM3
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: CLN6 c.150C>G (p.Tyr50X) 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 associated with Neuronal Ceroid Lipofuscinosis (NCL) in HGMD. The variant allele was found at a frequency of 8e-06 in 251404 control chromosomes. c.150C>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (DiFruscio_2015), and specifically in Kufs disease, a subtype of NCL (Arsov_2011, Talbot_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
Reported previously in a patient with a clinical diagnosis of Kufs disease who was also heterozygous for two missense substitutions in the CLN6 gene, although no further clinical details were provided and parental testing was not performed to determine the phase of the three variants (PMID: 21549341); Reported previously as a pathogenic variant in a cohort of patients referred for epilepsy genetic testing; however, no specific clinical information was provided (PMID: 31440721); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 31440721, 26075876, 33024953, 21549341)
Comment:
This sequence change creates a premature translational stop signal (p.Tyr50*) in the CLN6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN6 are known to be pathogenic (PMID: 19135028). This variant is present in population databases (rs154774640, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21549341, 26075876). ClinVar contains an entry for this variant (Variation ID: 68094). For these reasons, this variant has been classified as Pathogenic.
Comment:
CLN6: PVS1, PM2, PM3
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| p.Asn77Lys homozygous CLN6 mutation in two unrelated Japanese patients with Kufs disease, an adult onset neuronal ceroid lipofuscinosis. | Onodera M | Clinica chimica acta; international journal of clinical chemistry | 2021 | PMID: 34597687 |
| Moyamoya and progressive myoclonic epilepsy secondary to CLN6 bi-allelic mutations - A previously unreported association. | Talbot J | Epilepsy & behavior reports | 2020 | PMID: 33024953 |
| Novel mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis without visual impairment in two unrelated patients. | Chin JJ | Molecular genetics and metabolism | 2019 | PMID: 30528883 |
| Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. | Robak LA | Brain : a journal of neurology | 2017 | PMID: 29140481 |
| Lysoplex: An efficient toolkit to detect DNA sequence variations in the autophagy-lysosomal pathway. | Di Fruscio G | Autophagy | 2015 | PMID: 26075876 |
| Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations. | Mancini C | Journal of neurology | 2015 | PMID: 25359263 |
| 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 |
| Same gene, surprising difference: adult neuronal ceroid lipofuscinosis linked to CLN6, mutated in variant late-infantile form. | Kay C | Clinical genetics | 2011 | PMID: 21819394 |
| Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6. | Arsov T | American journal of human genetics | 2011 | PMID: 21549341 |
| Variant late infantile ceroid lipofuscinoses associated with novel mutations in CLN6. | Cannelli N | Biochemical and biophysical research communications | 2009 | PMID: 19135028 |
Text-mined citations for rs154774640 ...
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 May 25, 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.