VCV000056536.10 - ClinVar

NM_006493.4(CLN5):c.377T>G (p.Leu126Ter)

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.377T>G (p.Leu126Ter)

Variation ID: 56536 Accession: VCV000056536.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q22.3 13: 76995939 (GRCh38) [ NCBI UCSC ] 13: 77570074 (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	Feb 20, 2024	Dec 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006493.4:c.377T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006484.2:p.Leu126Ter	nonsense
NM_001366624.2:c.377T>G	NP_001353553.1:p.Leu126Ter	nonsense
NC_000013.11:g.76995939T>G
NC_000013.10:g.77570074T>G
NG_009064.1:g.9016T>G
LRG_692:g.9016T>G
LRG_692t1:c.524T>G

... more HGVS ... less HGVS

Protein change

L126*

Other names

Canonical SPDI

NC_000013.11:76995938:T:G

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 0.00000

Links

ClinGen: CA263891 dbSNP: rs386833972 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	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.
Neuronal ceroid lipofuscinosis 5	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 10, 2021	RCV000049949.9
Neuronal ceroid lipofuscinosis	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 25, 2023	RCV002265586.4

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: SCV001977477.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely pathogenic (May 25, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002548415.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022	Publications: PubMed (1) PubMed: 21990111 Comment: Variant summary: CLN5 c.524T>G (p.Leu175X) 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.524T>G (p.Leu175X) 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 4e-06 in 251486 control chromosomes (gnomAD). c.524T>G has been reported in the literature in at least one homozygous individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease, Kousi_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Likely pathogenic (Sep 16, 2014)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: literature only	Ceroid lipofuscinosis neuronal 5 (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220699.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 21990111
Pathogenic (Dec 25, 2023)	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: SCV003509857.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 20157158‚ 21990111 Comment: This sequence change creates a premature translational stop signal (p.Leu175) in the CLN5 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Leu175) in the CLN5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN5 are known to be pathogenic (PMID: 20157158). This variant is present in population databases (rs386833972, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21990111). ClinVar contains an entry for this variant (Variation ID: 56536). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ceroid lipofuscinosis neuronal 5 Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000588366.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: Persian Geographic origin: Iran
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: SCV000082358.1 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:

Variant summary: CLN5 c.524T>G (p.Leu175X) 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 4e-06 in 251486 control chromosomes (gnomAD). c.524T>G has been reported in the literature in at least one homozygous individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease, Kousi_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Leu175*) in the CLN5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN5 are known to be pathogenic (PMID: 20157158). This variant is present in population databases (rs386833972, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21990111). ClinVar contains an entry for this variant (Variation ID: 56536). 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
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

Text-mined citations for rs386833972 ...

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.377T>G (p.Leu126Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs386833972 ...