ClinVar Genomic variation as it relates to human health
NM_018941.4(CLN8):c.473A>G (p.Tyr158Cys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_018941.4(CLN8):c.473A>G (p.Tyr158Cys)
Variation ID: 56710 Accession: VCV000056710.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8p23.3 8: 1771527 (GRCh38) [ NCBI UCSC ] 8: 1719693 (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 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018941.4:c.473A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_061764.2:p.Tyr158Cys missense NC_000008.11:g.1771527A>G NC_000008.10:g.1719693A>G NG_008656.2:g.20750A>G LRG_691:g.20750A>G LRG_691t1:c.473A>G LRG_691p1:p.Tyr158Cys Q9UBY8:p.Tyr158Cys - Protein change
- Y158C
- Other names
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- Canonical SPDI
- NC_000008.11:1771526:A:G
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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CLN8 | - | - |
GRCh38 GRCh38 GRCh37 |
537 | 697 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, single submitter
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- | RCV000050123.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 6, 2023 | RCV001377678.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 25, 2021 | RCV002483067.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 15, 2022 | RCV002514269.1 |
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
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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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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 8
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820212.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
The missense variant c.473A>G (p.Tyr158Cys) in CLN8 gene has been previously observed in individual(s) with neuronal ceroid lipofuscinosis (Cannelli et al. 2006, Kousi et al. … (more)
The missense variant c.473A>G (p.Tyr158Cys) in CLN8 gene has been previously observed in individual(s) with neuronal ceroid lipofuscinosis (Cannelli et al. 2006, Kousi et al. 2012). In at least one individual the data is consistent with the variant being in trans from a pathogenic variant. This variant has been previously reported to affect CLN8 protein function (Vantaggiato et al. 2009). The p.Tyr158Cys variant is novel (not in any individuals) in 1000 Genomes and is present in the gnomAD exomes database with a frequency of 0.0008%. This variant has been reported to the ClinVar database as Likely Pathogenic. The amino acid Tyr at position 158 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Tyr158Cys in CLN8 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Delayed speech and language development (present) , Focal-onset seizure (present) , Developmental regression (present) , Difficulty walking (present) , Neck muscle weakness (present) , Progressive … (more)
Delayed speech and language development (present) , Focal-onset seizure (present) , Developmental regression (present) , Difficulty walking (present) , Neck muscle weakness (present) , Progressive language deterioration (present) (less)
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Likely pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003559699.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.473A>G (p.Y158C) alteration is located in exon 2 (coding exon 1) of the CLN8 gene. This alteration results from a A to G substitution … (more)
The c.473A>G (p.Y158C) alteration is located in exon 2 (coding exon 1) of the CLN8 gene. This alteration results from a A to G substitution at nucleotide position 473, causing the tyrosine (Y) at amino acid position 158 to be replaced by a cysteine (C). Based on data from gnomAD, the G allele has an overall frequency of <0.01% (2/251456) total alleles studied. The highest observed frequency was <0.01% (1/30616) of South Asian alleles. This alteration has been detected in the homozygous state, and in conjunction with another pathogenic mutation in CLN8, in several unrelated individuals with CLN8-related neuronal ceroid lipofuscinosis (Kousi, 2012; Cannelli, 2006; Di Fruscio, 2015; Jilani, 2019). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001575070.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 158 of the CLN8 protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 158 of the CLN8 protein (p.Tyr158Cys). This variant is present in population databases (rs386834130, gnomAD 0.003%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 16570191, 21990111). 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: 56710). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLN8 protein function. Experimental studies have shown that this missense change affects CLN8 function (PMID: 19431184). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 8
Neuronal ceroid lipofuscinosis 8 northern epilepsy variant
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002787476.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223391.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: CLN8 c.473A>G (p.Tyr158Cys) results in a non-conservative amino acid change located in the TRAM/LAG1/CLN8 homology domain (IPR006634) of the encoded protein sequence. Five … (more)
Variant summary: CLN8 c.473A>G (p.Tyr158Cys) results in a non-conservative amino acid change located in the TRAM/LAG1/CLN8 homology domain (IPR006634) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251456 control chromosomes (gnomAD). c.473A>G has been reported in the literature in multiple individuals affected with CLN8-related neuronal ceroid lipofuscinosis (examples: Cannelli_2006, DiFruscio_2015, Jilani_2019, Sharkia_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16570191, 26075876, 36011304, 31741823). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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 8
Affected status: not provided
Allele origin:
not provided
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082533.1
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
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Comment:
Converted during submission to Likely pathogenic.
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Likely pathogenic
(Oct 06, 2020)
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no assertion criteria provided
Method: clinical testing
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Neuronal ceroid lipofuscinosis 8
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002083175.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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CLN8 Gene Compound Heterozygous Variants: A New Case and Protein Bioinformatics Analyses. | Sharkia R | Genes | 2022 | PMID: 36011304 |
High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses. | Jilani A | JIMD reports | 2019 | PMID: 31741823 |
Lysoplex: An efficient toolkit to detect DNA sequence variations in the autophagy-lysosomal pathway. | Di Fruscio G | Autophagy | 2015 | PMID: 26075876 |
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 |
A novel CLN8 mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function. | Vantaggiato C | Human mutation | 2009 | PMID: 19431184 |
Novel mutations in CLN8 in Italian variant late infantile neuronal ceroid lipofuscinosis: Another genetic hit in the Mediterranean. | Cannelli N | Neurogenetics | 2006 | PMID: 16570191 |
Text-mined citations for rs386834130 ...
HelpRecord last updated Apr 06, 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.