Variant summary: CLN5 c.924_925delAT (p.Phe309SerfsX12) 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 3.6e-05 in 251266 control chromosomes, predominantly at a frequency of 0.00026 within the Latino subpopulation in the gnomAD database. c.924_925delAT has been reported in the literature in one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_006493.4(CLN5):c.777_778del (p.Phe260fs)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
6 out of 7 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.
7
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006493.4(CLN5):c.777_778del (p.Phe260fs)
Variation ID: 189038 Accession: VCV000189038.24
- Type and length
-
Microsatellite, 2 bp
- Location
-
Cytogenetic: 13q22.3 13: 77000667-77000668 (GRCh38) [ NCBI UCSC ] 13: 77574802-77574803 (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 Mar 29, 2015 Jul 5, 2025 Sep 3, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006493.4:c.777_778del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006484.2:p.Phe260fs frameshift NM_001366624.2:c.*224AT[1] 3 prime UTR NM_006493.2:c.924_925del NC_000013.11:g.77000667AT[1] NC_000013.10:g.77574802AT[1] NG_009064.1:g.13744AT[1] LRG_692:g.13744AT[1] LRG_692t1:c.924_925del - Protein change
- F260fs
- Other names
- -
- Canonical SPDI
- NC_000013.11:77000666:ATAT:AT
-
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.
- -
- 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 |
629 | 838 | |
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
|
Oct 9, 2023 | RCV000169429.8 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 3, 2024 | RCV000468638.12 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 19, 2024 | RCV000413943.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 22, 2020 | RCV002372061.2 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(May 19, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919231.2
First in ClinVar: Jun 02, 2019 Last updated: Jul 17, 2022 |
Comment:
show
Variant summary: CLN5 c.924_925delAT (p.Phe309SerfsX12) 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 3.6e-05 in 251266 control chromosomes, predominantly at a frequency of 0.00026 within the Latino subpopulation in the gnomAD database. c.924_925delAT has been reported in the literature in one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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
|
|
|
Likely pathogenic
(Jul 19, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000491175.5
First in ClinVar: Jan 09, 2017 Last updated: Sep 16, 2024 |
Comment:
show
Frameshift variant predicted to result in abnormal protein length as the last 99 amino acids are replaced with 11 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 22532218, 31440721, 20157158) (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
(Sep 03, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000549225.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 25, 2025 |
Comment:
show
This sequence change creates a premature translational stop signal (p.Phe309Serfs*12) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs769059034, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 22532218). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189038). This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392*) have been determined to be pathogenic (PMID: 9662406). 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)
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
(Aug 04, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis 5 |
Fulgent Genetics, Fulgent Genetics
Accession: SCV002804825.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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
(Oct 09, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis 5 |
Baylor Genetics
Accession: SCV004214371.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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 22, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Inborn genetic diseases |
Ambry Genetics
Accession: SCV002687621.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
show
The c.924_925delAT pathogenic mutation, located in coding exon 4 of the CLN5 gene, results from a deletion of two nucleotides at nucleotide positions 924 to 925, causing a translational frameshift with a predicted alternate stop codon (p.F309Sfs*12). This alteration was detected in trans with a second truncating alteration in CLN5 in an individual with neuronal ceroid lipofuscinosis (NCL) (Pérez-Poyato M S et al. Rev Neurol, 2012 May;54:544-50). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. (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
|
|
|
Likely pathogenic
(Oct 27, 2014)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Ceroid lipofuscinosis neuronal 5
(Autosomal recessive inheritance)
|
Counsyl
Accession: SCV000220840.3
First in ClinVar: Mar 29, 2015 Last updated: Jul 05, 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: literature only
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: literature only
Allele origin: unknown
Affected status: unknown
|
|
Comment:
Comment:
Frameshift variant predicted to result in abnormal protein length as the last 99 amino acids are replaced with 11 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 22532218, 31440721, 20157158)
Comment:
This sequence change creates a premature translational stop signal (p.Phe309Serfs*12) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs769059034, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 22532218). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189038). This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392*) have been determined to be pathogenic (PMID: 9662406). 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:
The c.924_925delAT pathogenic mutation, located in coding exon 4 of the CLN5 gene, results from a deletion of two nucleotides at nucleotide positions 924 to 925, causing a translational frameshift with a predicted alternate stop codon (p.F309Sfs*12). This alteration was detected in trans with a second truncating alteration in CLN5 in an individual with neuronal ceroid lipofuscinosis (NCL) (Pérez-Poyato M S et al. Rev Neurol, 2012 May;54:544-50). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| [Neuronal ceroid lipofuscinosis: diagnostic algorithm and clinical description of the Finnish (CLN5) and Turkish (CLN7) variants late infantile]. | Pérez-Poyato M S | Revista de neurologia | 2012 | PMID: 22532218 |
| 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 rs786204644 ...
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 Jul 05, 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.