VCV000056543.15 - ClinVar

NM_006493.4(CLN5):c.522dup (p.Trp175fs)

Germline

Classification

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)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006493.4(CLN5):c.522dup (p.Trp175fs)

Variation ID: 56543 Accession: VCV000056543.15

Type and length

Duplication, 1 bp

Location

Cytogenetic: 13q22.3 13: 76996083-76996084 (GRCh38) [ NCBI UCSC ] 13: 77570218-77570219 (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 17, 2024	Feb 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006493.4:c.522dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006484.2:p.Trp175fs	frameshift
NM_001366624.2:c.522dup	NP_001353553.1:p.Trp175fs	frameshift
NC_000013.11:g.76996084dup
NC_000013.10:g.77570219dup
NG_009064.1:g.9161dup
LRG_692:g.9161dup
LRG_692t1:c.669dup

... more HGVS ... less HGVS

Protein change

W175fs

Other names

Canonical SPDI

NC_000013.11:76996083:C:CC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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), exomes 0.00003

Exome Aggregation Consortium (ExAC) 0.00007

Links

ClinGen: CA263910 dbSNP: rs386833979 VarSome

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
Gene	OMIM	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	598	798

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.
Neuronal ceroid lipofuscinosis 5	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 7, 2024	RCV000049956.6
Neuronal ceroid lipofuscinosis	Pathogenic (2)	criteria provided, single submitter	Apr 16, 2022	RCV000690321.9

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.
Pathogenic (Aug 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 5 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001977481.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely pathogenic (May 16, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Neuronal ceroid lipofuscinosis 5 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000486348.2 First in ClinVar: Jul 24, 2013 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 20052765‚ 10953198‚ 21990111
Pathogenic (Feb 07, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 5 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004214389.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Apr 16, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neuronal ceroid lipofuscinosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000818003.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 28492532‚ 21990111‚ 20052765‚ 20157158‚ 20960652‚ 22532218‚ 25976102 Comment: This sequence change creates a premature translational stop signal (p.Trp224Leufs30) 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.Trp224Leufs30) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 184 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs770949806, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21990111; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.669insC and p.E253X. ClinVar contains an entry for this variant (Variation ID: 56543). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CLN5 function (PMID: 20052765). This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Lys368Serfs*15) have been determined to be pathogenic (PMID: 20157158, 20960652, 22532218, 25976102; Invitae). 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)
probable-pathogenic (-)	no assertion criteria provided Method: not provided	Ceroid lipofuscinosis neuronal 5 Affected status: not provided Allele origin: not provided	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) Accession: SCV000082365.1 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.
Pathogenic (Aug 20, 2021)	no assertion criteria provided Method: clinical testing	Neuronal ceroid lipofuscinosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002087970.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This sequence change creates a premature translational stop signal (p.Trp224Leufs*30) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 184 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs770949806, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21990111; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.669insC and p.E253X. ClinVar contains an entry for this variant (Variation ID: 56543). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CLN5 function (PMID: 20052765). This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Lys368Serfs*15) have been determined to be pathogenic (PMID: 20157158, 20960652, 22532218, 25976102; Invitae). 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.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The neuronal ceroid lipofuscinoses program: A translational research experience in Argentina.	Kohan R	Biochimica et biophysica acta	2015	PMID: 25976102
[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
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
Gene symbol: CLN5. Disease: Neuronal Ceroid Lipofuscinosis, finnish variant.	Kohan R	Human genetics	2008	PMID: 20960652
Phenotype-genotype correlation in eight patients with Finnish variant late infantile NCL (CLN5).	Holmberg V	Neurology	2000	PMID: 10953198

Text-mined citations for rs386833979 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_006493.4(CLN5):c.522dup (p.Trp175fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs386833979 ...