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: 20026029, 10190325, 8817339, 16134170, 11735028)
ClinVar Genomic variation as it relates to human health
NM_001352514.2(HLCS):c.2152G>A (p.Asp718Asn)
Germline
Classification
Help
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.
(8)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(2); Uncertain significance(2)
Pathogenic(2); Likely pathogenic(2); Uncertain significance(2)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001352514.2(HLCS):c.2152G>A (p.Asp718Asn)
Variation ID: 1908 Accession: VCV000001908.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 21q22.13 21: 36759811 (GRCh38) [ NCBI UCSC ] 21: 38132112 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Jun 17, 2024 Mar 26, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001352514.2:c.2152G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001339443.1:p.Asp718Asn missense NM_000411.8:c.1711G>A NP_000402.3:p.Asp571Asn missense NM_001242784.3:c.1711G>A NP_001229713.1:p.Asp571Asn missense NM_001242785.2:c.1711G>A NP_001229714.1:p.Asp571Asn missense NM_001352515.2:c.1711G>A NP_001339444.1:p.Asp571Asn missense NM_001352516.2:c.1711G>A NP_001339445.1:p.Asp571Asn missense NM_001352517.1:c.1711G>A NP_001339446.1:p.Asp571Asn missense NM_001352518.2:c.1711G>A NP_001339447.1:p.Asp571Asn missense NR_148020.2:n.2011G>A non-coding transcript variant NR_148021.1:n.2168G>A non-coding transcript variant NC_000021.9:g.36759811C>T NC_000021.8:g.38132112C>T NG_016193.2:g.235584G>A P50747:p.Asp571Asn - Protein change
- D571N, D718N
- Other names
- -
- Canonical SPDI
- NC_000021.9:36759810:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00006
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- 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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| HLCS | - | - |
GRCh38 GRCh37 |
970 | 1064 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
|
Mar 26, 2024 | RCV000001985.25 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 10, 2023 | RCV003328550.1 |
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 07, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
paternal
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000782518.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
|
Uncertain significance
(Jan 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000800478.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
|
Likely pathogenic
(Mar 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004035699.1
First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023 |
Comment:
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; … (more)
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: 20026029, 10190325, 8817339, 16134170, 11735028) (less)
|
|
|
Uncertain significance
(Nov 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914969.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The HLCS c.1711G>A (p.Asp571Asn) variant has been reported in four studies and is found in a total of at least two patients in a compound … (more)
The HLCS c.1711G>A (p.Asp571Asn) variant has been reported in four studies and is found in a total of at least two patients in a compound heterozygous state (Dupuis et al. 1996; Aoki et al. 1999; Yang et al. 2001; Suzuki et al. 2005). Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Genome Aggregation Database. Transient expression of the p.Asp571Asn variant, which occurs at a highly conserved residue in a putative biotin-binding region in transformed patient fibroblasts resulted in HCS enzyme activity of 0.1% that of the wild type enzyme (Aoki et al. 1999). Based on the evidence, the p.Asp571Asn variant is classified as a variant of unknown significance but suspicious for holocarboxylase synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Likely pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000834658.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 571 of the HLCS protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 571 of the HLCS protein (p.Asp571Asn). This variant is present in population databases (rs119103228, gnomAD 0.01%). This missense change has been observed in individuals with holocarboxylase synthetase deficiency (PMID: 8817339, 11735028). ClinVar contains an entry for this variant (Variation ID: 1908). 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 HLCS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HLCS function (PMID: 10068510, 10190325). 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)
|
|
|
Pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004199827.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Feb 01, 1999)
|
no assertion criteria provided
Method: literature only
|
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022143.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with multiple carboxylase deficiency (253270), Dupuis et al. (1996) identified a 1998G-A transition in the HLCS gene, resulting in an asp571-to-asn (D571N) … (more)
In a patient with multiple carboxylase deficiency (253270), Dupuis et al. (1996) identified a 1998G-A transition in the HLCS gene, resulting in an asp571-to-asn (D571N) substitution. Aoki et al. (1999) performed transient transfection studies in patient fibroblasts, which revealed that the D571N mutant protein had 0.1% of wildtype activity, suggesting that asp571 is crucial for catalytic activity. (less)
|
|
|
Likely pathogenic
(Sep 11, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Holocarboxylase synthetase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002083722.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
The HLCS c.1711G>A (p.Asp571Asn) variant has been reported in four studies and is found in a total of at least two patients in a compound heterozygous state (Dupuis et al. 1996; Aoki et al. 1999; Yang et al. 2001; Suzuki et al. 2005). Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Genome Aggregation Database. Transient expression of the p.Asp571Asn variant, which occurs at a highly conserved residue in a putative biotin-binding region in transformed patient fibroblasts resulted in HCS enzyme activity of 0.1% that of the wild type enzyme (Aoki et al. 1999). Based on the evidence, the p.Asp571Asn variant is classified as a variant of unknown significance but suspicious for holocarboxylase synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 571 of the HLCS protein (p.Asp571Asn). This variant is present in population databases (rs119103228, gnomAD 0.01%). This missense change has been observed in individuals with holocarboxylase synthetase deficiency (PMID: 8817339, 11735028). ClinVar contains an entry for this variant (Variation ID: 1908). 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 HLCS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HLCS function (PMID: 10068510, 10190325). 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.
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. |
Comment:
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: 20026029, 10190325, 8817339, 16134170, 11735028)
Comment:
The HLCS c.1711G>A (p.Asp571Asn) variant has been reported in four studies and is found in a total of at least two patients in a compound heterozygous state (Dupuis et al. 1996; Aoki et al. 1999; Yang et al. 2001; Suzuki et al. 2005). Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Genome Aggregation Database. Transient expression of the p.Asp571Asn variant, which occurs at a highly conserved residue in a putative biotin-binding region in transformed patient fibroblasts resulted in HCS enzyme activity of 0.1% that of the wild type enzyme (Aoki et al. 1999). Based on the evidence, the p.Asp571Asn variant is classified as a variant of unknown significance but suspicious for holocarboxylase synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 571 of the HLCS protein (p.Asp571Asn). This variant is present in population databases (rs119103228, gnomAD 0.01%). This missense change has been observed in individuals with holocarboxylase synthetase deficiency (PMID: 8817339, 11735028). ClinVar contains an entry for this variant (Variation ID: 1908). 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 HLCS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HLCS function (PMID: 10068510, 10190325). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The polypeptide Syn67 interacts physically with human holocarboxylase synthetase, but is not a target for biotinylation. | Hassan YI | Archives of biochemistry and biophysics | 2010 | PMID: 20026029 |
| Mutations in the holocarboxylase synthetase gene HLCS. | Suzuki Y | Human mutation | 2005 | PMID: 16134170 |
| Structure of human holocarboxylase synthetase gene and mutation spectrum of holocarboxylase synthetase deficiency. | Yang X | Human genetics | 2001 | PMID: 11735028 |
| Identification and characterization of mutations in patients with holocarboxylase synthetase deficiency. | Aoki Y | Human genetics | 1999 | PMID: 10190325 |
| Mechanism of biotin responsiveness in biotin-responsive multiple carboxylase deficiency. | Dupuis L | Molecular genetics and metabolism | 1999 | PMID: 10068510 |
| Clustering of mutations in the biotin-binding region of holocarboxylase synthetase in biotin-responsive multiple carboxylase deficiency. | Dupuis L | Human molecular genetics | 1996 | PMID: 8817339 |
Text-mined citations for rs119103228 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.