ClinVar Genomic variation as it relates to human health
NM_006493.4(CLN5):c.61C>T (p.Arg21Trp)
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.
Uncertain significance(6); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006493.4(CLN5):c.61C>T (p.Arg21Trp)
Variation ID: 205141 Accession: VCV000205141.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q22.3 13: 76992159 (GRCh38) [ NCBI UCSC ] 13: 77566294 (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 9, 2016 May 1, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006493.4:c.61C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006484.2:p.Arg21Trp missense NM_001366624.2:c.61C>T NP_001353553.1:p.Arg21Trp missense NC_000013.11:g.76992159C>T NC_000013.10:g.77566294C>T NG_009064.1:g.5236C>T LRG_692:g.5236C>T LRG_692t1:c.208C>T - Protein change
- R21W
- Other names
- p.R70W:CGG>TGG
- Canonical SPDI
- NC_000013.11:76992158:C:T
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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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0.00040 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00012
Exome Aggregation Consortium (ExAC) 0.00016
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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 | ||
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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
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. |
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CLN5 | - | - |
GRCh38 GRCh37 |
587 | 786 | |
LOC130009913 | - | - | - | GRCh38 | - | 152 |
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. |
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Uncertain significance (2) |
criteria provided, single submitter
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Jul 1, 2016 | RCV000187066.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000306509.5 | |
Uncertain significance (2) |
criteria provided, single submitter
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Aug 23, 2022 | RCV000553078.6 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 20, 2023 | RCV001111459.8 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 19, 2024 | RCV003298245.2 |
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. |
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. |
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Uncertain significance
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000384723.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Jul 01, 2016)
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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: SCV000240641.11
First in ClinVar: Aug 07, 2015 Last updated: Oct 09, 2016 |
Comment:
The R70W variant has not been publishedas a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R70W variant … (more)
The R70W variant has not been publishedas a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R70W variant was notobserved with any significant frequency in approximately 6,200 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports it was observed in 2/978(0.2%) alleles from individuals of South Asian background. The R70W variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, sizeand/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis isinconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore,based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benignvariant. (less)
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 5
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001269019.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Sep 05, 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: SCV002027053.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Uncertain significance
(Aug 23, 2022)
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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: SCV000628961.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 70 of the CLN5 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 70 of the CLN5 protein (p.Arg70Trp). This variant is present in population databases (rs376454715, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with CLN5-related conditions. ClinVar contains an entry for this variant (Variation ID: 205141). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Dec 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 5
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004235332.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely benign
(Jan 19, 2024)
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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: SCV004002174.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Jan 24, 2020)
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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: SCV001460315.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553784.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CLN5 p.R21W variant was not identified in the literature but was identified in dbSNP (ID: rs376454715) and ClinVar (classified as uncertain significance by Invitae, … (more)
The CLN5 p.R21W variant was not identified in the literature but was identified in dbSNP (ID: rs376454715) and ClinVar (classified as uncertain significance by Invitae, GeneDx and Illumina). The variant was identified in control databases in 26 of 222450 chromosomes at a frequency of 0.0001169 (Genome Aggregation Database March 6, 2019, v2.1.1). The pR21 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs376454715 ...
HelpRecord last updated May 01, 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.