Variant summary: CLN5 c.936delT (p.Phe312LeufsX4) 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 allele was found at a frequency of 1.2e-05 in 246982 control chromosomes. c.1083delT has been reported in the literature as a homozygous genotype in at-least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and has been subsequently cited by others (example, Xin_2010, Ge_2018, Kousi_2012, Luo_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_006493.4(CLN5):c.936del (p.Phe312fs)
Germline
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.
(5)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006493.4(CLN5):c.936del (p.Phe312fs)
Variation ID: 56528 Accession: VCV000056528.11
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 13q22.3 13: 77000824 (GRCh38) [ NCBI UCSC ] 13: 77574959 (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 Jul 24, 2013 Feb 14, 2024 Nov 25, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006493.4:c.936del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006484.2:p.Phe312fs frameshift NM_006493.4:c.936delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001366624.2:c.*385del 3 prime UTR NC_000013.11:g.77000828del NC_000013.10:g.77574963del NG_009064.1:g.13905del LRG_692:g.13905del LRG_692t1:c.1083del - Protein change
- F312fs
- Other names
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- Canonical SPDI
- NC_000013.11:77000823:TTTTT:TTTT
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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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- 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. |
|||
| CLN5 | - | - |
GRCh38 GRCh37 |
597 | 796 | |
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
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Jul 21, 2023 | RCV000049941.4 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 25, 2023 | RCV000803462.8 |
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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Pathogenic
(Aug 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 5
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001977490.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
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Pathogenic
(Jul 13, 2022)
|
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: SCV001338973.3
First in ClinVar: Jun 22, 2020 Last updated: Sep 17, 2022 |
Comment:
Variant summary: CLN5 c.936delT (p.Phe312LeufsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: CLN5 c.936delT (p.Phe312LeufsX4) 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 allele was found at a frequency of 1.2e-05 in 246982 control chromosomes. c.1083delT has been reported in the literature as a homozygous genotype in at-least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and has been subsequently cited by others (example, Xin_2010, Ge_2018, Kousi_2012, Luo_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 5
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004214381.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
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Pathogenic
(Nov 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000943334.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Phe361Leufs*4) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Phe361Leufs*4) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs386833966, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (NCL) (PMID: 20157158). ClinVar contains an entry for this variant (Variation ID: 56528). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392*) have been determined to be pathogenic (PMID: 9662406, 11971870, 20052765, 24038957, 24058541). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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probable-pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Ceroid lipofuscinosis neuronal 5
Affected status: not provided
Allele origin:
not provided
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082350.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
|
Comment:
Converted during submission to Likely pathogenic.
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Phe361Leufs*4) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs386833966, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (NCL) (PMID: 20157158). ClinVar contains an entry for this variant (Variation ID: 56528). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392*) have been determined to be pathogenic (PMID: 9662406, 11971870, 20052765, 24038957, 24058541). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Converted during submission to Likely pathogenic.
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: CLN5 c.936delT (p.Phe312LeufsX4) 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 allele was found at a frequency of 1.2e-05 in 246982 control chromosomes. c.1083delT has been reported in the literature as a homozygous genotype in at-least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and has been subsequently cited by others (example, Xin_2010, Ge_2018, Kousi_2012, Luo_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories 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.Phe361Leufs*4) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs386833966, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (NCL) (PMID: 20157158). ClinVar contains an entry for this variant (Variation ID: 56528). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392*) have been determined to be pathogenic (PMID: 9662406, 11971870, 20052765, 24038957, 24058541). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Converted during submission to Likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Functional Analysis of a Novel CLN5 Mutation Identified in a Patient With Neuronal Ceroid Lipofuscinosis. | Luo S | Frontiers in genetics | 2020 | PMID: 32983231 |
| Novel Mutations in CLN5 of Chinese Patients With Neuronal Ceroid Lipofuscinosis. | Ge L | Journal of child neurology | 2018 | PMID: 30264640 |
| The role of N-glycosylation in folding, trafficking, and functionality of lysosomal protein CLN5. | Moharir A | PloS one | 2013 | PMID: 24058541 |
| Topology and membrane anchoring of the lysosomal storage disease-related protein CLN5. | Larkin H | Human mutation | 2013 | PMID: 24038957 |
| 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 |
| CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL. | Xin W | Neurology | 2010 | PMID: 20157158 |
| The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations. | Schmiedt ML | Human mutation | 2010 | PMID: 20052765 |
| Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein. | Isosomppi J | Human molecular genetics | 2002 | PMID: 11971870 |
| CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis. | Savukoski M | Nature genetics | 1998 | PMID: 9662406 |
Text-mined citations for rs386833966 ...
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 Sep 29, 2024
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.