ClinVar Genomic variation as it relates to human health
NM_001352514.2(HLCS):c.2527C>T (p.Gln843Ter)
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_001352514.2(HLCS):c.2527C>T (p.Gln843Ter)
Variation ID: 553590 Accession: VCV000553590.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.13 21: 36754341 (GRCh38) [ NCBI UCSC ] 21: 38126642 (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 Aug 5, 2018 Jan 25, 2025 Jun 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001352514.2:c.2527C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001339443.1:p.Gln843Ter nonsense NM_000411.8:c.2086C>T NP_000402.3:p.Gln696Ter nonsense NM_001242784.3:c.2086C>T NP_001229713.1:p.Gln696Ter nonsense NM_001242785.2:c.2086C>T NP_001229714.1:p.Gln696Ter nonsense NM_001352515.2:c.2086C>T NP_001339444.1:p.Gln696Ter nonsense NM_001352516.2:c.2086C>T NP_001339445.1:p.Gln696Ter nonsense NM_001352517.1:c.2086C>T NP_001339446.1:p.Gln696Ter nonsense NM_001352518.2:c.2086C>T NP_001339447.1:p.Gln696Ter nonsense NR_148020.2:n.2611C>T non-coding transcript variant NR_148021.1:n.2768C>T non-coding transcript variant NC_000021.9:g.36754341G>A NC_000021.8:g.38126642G>A NG_016193.2:g.241054C>T - Protein change
- Q696*, Q843*
- Other names
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- Canonical SPDI
- NC_000021.9:36754340: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), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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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HLCS | - | - |
GRCh38 GRCh37 |
982 | 1078 |
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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Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 24, 2024 | RCV000669070.6 |
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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Likely pathogenic
(Aug 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000793771.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely pathogenic
(Mar 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003003599.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This variant disrupts a region of the HLCS protein in which other variant(s) (p.Pro709Leu) have been observed in individuals with HLCS-related conditions (PMID: 27604308). This … (more)
This variant disrupts a region of the HLCS protein in which other variant(s) (p.Pro709Leu) have been observed in individuals with HLCS-related conditions (PMID: 27604308). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that this premature translational stop signal affects HLCS function (PMID: 11124959). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 553590). This variant is also known as a 31-amino acid deletion ending at Leu-695. This variant has not been reported in the literature in individuals affected with HLCS-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Gln696*) in the HLCS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the HLCS protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Mar 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005059682.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Jun 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
germline
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Fulgent Genetics, Fulgent Genetics
Accession: SCV005664084.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
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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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Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes. | Reid ES | Brain : a journal of neurology | 2016 | PMID: 27604308 |
Expression in Escherichia coli of N- and C-terminally deleted human holocarboxylase synthetase. Influence of the N-terminus on biotinylation and identification of a minimum functional protein. | Campeau E | The Journal of biological chemistry | 2001 | PMID: 11124959 |
Text-mined citations for rs1466111134 ...
HelpRecord last updated Feb 01, 2025
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.