ClinVar Genomic variation as it relates to human health
NM_001352514.2(HLCS):c.2134C>T (p.Arg712Ter)
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.2134C>T (p.Arg712Ter)
Variation ID: 426486 Accession: VCV000426486.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.13 21: 36759829 (GRCh38) [ NCBI UCSC ] 21: 38132130 (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 May 22, 2017 Jun 17, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001352514.2:c.2134C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001339443.1:p.Arg712Ter nonsense NM_000411.8:c.1693C>T NP_000402.3:p.Arg565Ter nonsense NM_001242784.3:c.1693C>T NP_001229713.1:p.Arg565Ter nonsense NM_001242785.2:c.1693C>T NP_001229714.1:p.Arg565Ter nonsense NM_001352515.2:c.1693C>T NP_001339444.1:p.Arg565Ter nonsense NM_001352516.2:c.1693C>T NP_001339445.1:p.Arg565Ter nonsense NM_001352517.1:c.1693C>T NP_001339446.1:p.Arg565Ter nonsense NM_001352518.2:c.1693C>T NP_001339447.1:p.Arg565Ter nonsense NR_148020.2:n.1993C>T non-coding transcript variant NR_148021.1:n.2150C>T non-coding transcript variant NC_000021.9:g.36759829G>A NC_000021.8:g.38132130G>A NG_016193.2:g.235566C>T - Protein change
- R565*, R712*
- Other names
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- Canonical SPDI
- NC_000021.9:36759828: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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Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- 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
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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 |
970 | 1064 |
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
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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Pathogenic (1) |
criteria provided, single submitter
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Apr 14, 2017 | RCV000489166.1 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000668883.16 |
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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Pathogenic
(Apr 14, 2017)
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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: SCV000576938.4
First in ClinVar: May 22, 2017 Last updated: May 22, 2017 |
Comment:
The R565X nonsense variant in the HLCS gene has been reported previously in association with holocarboxylase synthetase deciency in several unrelated individuals who were heterozygous … (more)
The R565X nonsense variant in the HLCS gene has been reported previously in association with holocarboxylase synthetase deciency in several unrelated individuals who were heterozygous for R565X and another variant in the HLCS gene (Sakamoto et al., 1998; Tang et al., 2003; Donti et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. (less)
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Pathogenic
(Aug 03, 2018)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919517.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: HLCS c.1693C>T (p.Arg565X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: HLCS c.1693C>T (p.Arg565X) 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. The variant allele was found at a frequency of 2e-05 in 246268 control chromosomes. c.1693C>T has been reported in the literature in individuals affected with Holocarboxylase Synthetase Deficiency (Sakamoto 1998, Tang 2003, Donti 2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Sakamoto_1998). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 31, 2022)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002777375.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 06, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002024999.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jun 12, 2023)
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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: SCV001589928.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 426486). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 426486). This premature translational stop signal has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 9870216). This variant is present in population databases (rs772791252, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg565*) in the HLCS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HLCS are known to be pathogenic (PMID: 16134170). (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Holocarboxylase synthetase deficiency
Affected status: no
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051835.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Jan 16, 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: SCV004199835.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Aug 18, 2017)
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no assertion criteria provided
Method: clinical testing
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Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000793557.2
First in ClinVar: Aug 05, 2018 Last updated: Jun 02, 2019 |
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Pathogenic
(Oct 30, 2020)
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no assertion criteria provided
Method: clinical testing
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Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002083725.1
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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Holocarboxylase synthetase deficiency pre and post newborn screening. | Donti TR | Molecular genetics and metabolism reports | 2016 | PMID: 27114915 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Mutations in the holocarboxylase synthetase gene HLCS. | Suzuki Y | Human mutation | 2005 | PMID: 16134170 |
A genomic approach to mutation analysis of holocarboxylase synthetase gene in three Chinese patients with late-onset holocarboxylase synthetase deficiency. | Tang NL | Clinical biochemistry | 2003 | PMID: 12633764 |
Molecular analysis of new Japanese patients with holocarboxylase synthetase deficiency. | Sakamoto O | Journal of inherited metabolic disease | 1998 | PMID: 9870216 |
Text-mined citations for rs772791252 ...
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.