ClinVar Genomic variation as it relates to human health
NM_006493.4(CLN5):c.188G>A (p.Arg63His)
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_006493.4(CLN5):c.188G>A (p.Arg63His)
Variation ID: 2567 Accession: VCV000002567.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q22.3 13: 76995077 (GRCh38) [ NCBI UCSC ] 13: 77569212 (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 Oct 23, 2016 Feb 14, 2024 Jan 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006493.4:c.188G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006484.2:p.Arg63His missense NM_001366624.2:c.188G>A NP_001353553.1:p.Arg63His missense NC_000013.11:g.76995077G>A NC_000013.10:g.77569212G>A NG_009064.1:g.8154G>A LRG_692:g.8154G>A LRG_692t1:c.335G>A LRG_692p1:p.Arg112His - Protein change
- R63H
- Other names
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R112H
- Canonical SPDI
- NC_000013.11:76995076:G:A
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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.
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The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
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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CLN5 | - | - |
GRCh38 GRCh37 |
597 | 796 |
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
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
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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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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 10, 2021 | RCV000002676.9 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 15, 2024 | RCV000698933.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 6, 2023 | RCV003128567.1 |
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
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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
(Feb 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003805402.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect as the R112H variant produces a protein unable to exit the endoplasmic reticulum (Schmiedt et al., 2010); Not … (more)
Published functional studies demonstrate a damaging effect as the R112H variant produces a protein unable to exit the endoplasmic reticulum (Schmiedt et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21990111, 15728307, 33792748, 30264640, 28542837, 30078242, 32983231, 20052765) (less)
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Likely pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 5
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001977461.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 5
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001530515.2
First in ClinVar: Mar 22, 2021 Last updated: Mar 18, 2023 |
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Likely pathogenic
(Aug 28, 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: SCV004037644.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: CLN5 c.188G>A (p.Arg63His), also referred to as p.Arg112His, results in a non-conservative amino acid change in the encoded protein sequence. Five of five … (more)
Variant summary: CLN5 c.188G>A (p.Arg63His), also referred to as p.Arg112His, results in a non-conservative amino acid change in 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 251186 control chromosomes (gnomAD). c.188G>A has been reported in the literature in the homozygous state in two siblings and in at least one other unrelated individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Pineda-Trujilo_2005, Zhou_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant protein primarily localizes to the ER as opposed to the lysosome, however, it does not allow convincing conclusions about the variant effect (Schmiedt_2010). Other variants affecting the same amino acid (i.e. p.Arg63Cys, p.Arg63Pro) have been reported in association with Neuronal Ceroid-Lipofuscinosis in the HGMD database, suggesting Arg63 may be important for protein function, but this has yet to be determined conclusively. The following publications have been ascertained in the context of this evaluation (PMID: 15728307, 20052765, 30078242). 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 likely pathogenic. (less)
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Pathogenic
(Jan 15, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000827624.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 112 of the CLN5 protein (p.Arg112His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 112 of the CLN5 protein (p.Arg112His). This variant is present in population databases (rs104894386, gnomAD 0.003%). This missense change has been observed in individuals with juvenile onset neuronal ceroid lipofuscinosis (PMID: 15728307, 28542837, 30078242). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2567). 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 expected to disrupt CLN5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CLN5 function (PMID: 20052765). This variant disrupts the p.Arg112 amino acid residue in CLN5. Other variant(s) that disrupt this residue have been observed in individuals with CLN5-related conditions (PMID: 30078242), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 22, 2005)
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no assertion criteria provided
Method: literature only
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CEROID LIPOFUSCINOSIS, NEURONAL, 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022834.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016 |
Comment on evidence:
In affected members of a large consanguineous Colombian family with juvenile-onset neuronal ceroid lipofuscinosis-5 (CLN5; 256731), Pineda-Trujillo et al. (2005) identified a homozygous 1627G-A transition … (more)
In affected members of a large consanguineous Colombian family with juvenile-onset neuronal ceroid lipofuscinosis-5 (CLN5; 256731), Pineda-Trujillo et al. (2005) identified a homozygous 1627G-A transition in the CLN5 gene, resulting in an arg112-to-his (R112H) substitution. The mutation occurs in a residue conserved among rodent, amphibian, and bird species, and was not identified in 58 control chromosomes. Onset of the disorder was at age 9 years, consistent with juvenile onset. The findings showed that the disorder occurs outside of northern Europe. (less)
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Likely pathogenic
(Apr 09, 2021)
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no assertion criteria provided
Method: clinical testing
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Neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002087951.1
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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[Clinical features and genetics studies of Finnish variant late infantile neuronal ceroid lipofuscinosis in two families]. | Zhou ZZ | Zhonghua er ke za zhi = Chinese journal of pediatrics | 2018 | PMID: 30078242 |
Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5. | Simonati A | Developmental medicine and child neurology | 2017 | PMID: 28542837 |
The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations. | Schmiedt ML | Human mutation | 2010 | PMID: 20052765 |
A CLN5 mutation causing an atypical neuronal ceroid lipofuscinosis of juvenile onset. | Pineda-Trujillo N | Neurology | 2005 | PMID: 15728307 |
Text-mined citations for rs104894386 ...
HelpRecord 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.