ClinVar Genomic variation as it relates to human health
NM_000190.4(HMBS):c.532G>A (p.Asp178Asn)
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.
Pathogenic(2); Likely pathogenic(2); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000190.4(HMBS):c.532G>A (p.Asp178Asn)
Variation ID: 372379 Accession: VCV000372379.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.3 11: 119091446 (GRCh38) [ NCBI UCSC ] 11: 118962156 (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 Jan 9, 2017 Jul 15, 2024 Aug 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000190.4:c.532G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000181.2:p.Asp178Asn missense NM_001024382.2:c.481G>A NP_001019553.1:p.Asp161Asn missense NM_001258208.2:c.532G>A NP_001245137.1:p.Asp178Asn missense NM_001258209.2:c.481G>A NP_001245138.1:p.Asp161Asn missense NC_000011.10:g.119091446G>A NC_000011.9:g.118962156G>A NG_008093.1:g.11570G>A LRG_1076:g.11570G>A LRG_1076t1:c.532G>A LRG_1076p1:p.Asp178Asn LRG_1076t2:c.481G>A LRG_1076p2:p.Asp161Asn - Protein change
- D161N, D178N
- Other names
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- Canonical SPDI
- NC_000011.10:119091445: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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0.00060 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00060
Exome Aggregation Consortium (ExAC) 0.00145
The Genome Aggregation Database (gnomAD) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00002
1000 Genomes Project 30x 0.00047
The Genome Aggregation Database (gnomAD), exomes 0.00050
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
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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HMBS | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
589 | 635 |
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
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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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 4, 2022 | RCV000413917.6 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Aug 1, 2023 | RCV000779045.14 |
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
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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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Likely pathogenic
(Nov 22, 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: SCV000490556.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Comment:
The D178N variant in the HMBS gene has been reported previously in the heterozygous state, in individuals with acute intermittent porphyria and some asymptomatic relatives … (more)
The D178N variant in the HMBS gene has been reported previously in the heterozygous state, in individuals with acute intermittent porphyria and some asymptomatic relatives (Puy et al., 1997; Floderus et al., 2002; Ulbrichova et al., 2009). Although the D178N variant was not observed in approximately 5700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, the 1000 Genomes Project reports D178N was observed in 3/978 (0.31%) alleles from individuals of South Asian background and the D178N variant is reported in 29/7912 (0.37%) alleles in the Exome Aggregation Consortium (ExAC) data set. The D178N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies comparing activity levels of the wild type HMBS enzyme to the D178N variant enzyme demonstrate the variant enzyme activity is reduced to 81% (Ulbrichova et al., 2009). Therefore, we interpret D178N as a likely pathogenic variant. (less)
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Uncertain significance
(Nov 20, 2018)
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criteria provided, single submitter
Method: clinical testing
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Acute intermittent porphyria
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915503.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The HMBS c.532G>A (p.Asp178Asn) missense variant has been reported in three studies in which it is found in a heterozygous state in at least three … (more)
The HMBS c.532G>A (p.Asp178Asn) missense variant has been reported in three studies in which it is found in a heterozygous state in at least three individuals with acute intermittent porphyria (Puy et al. 1997; Floderus et al. 2002; Ulbrichova et al. 2009). The asymptomatic mother of one of these individuals was also heterozygous for the p.Asp178Asn variant. Control data are not available for this variant which is reported at a frequency of 0.00367 in the South Asian population of the Exome Aggregation Consortium with one homozygote reported in the South Asian population of the Genome Aggregation Database. Of note, some individuals with disease-causing mutations do not develop symptoms for this condition. In patients who do have symptoms, the condition may be misdiagnosed or underdiagnosed due to the nature of the symptoms which include episodes of abdominal pain, vomiting, constipation, and diarrhoea. Functional studies in E. coli containing the p.Asp178Asn variant demonstrated 81% HMBS activity compared to wild type. Optimal pH for this variant protein was shown to be 7.5 compared to pH of 8.2 for wild type and thermostability studies demonstrated a 70% loss of activity for the variant protein at 650C compared to a 20% loss of activity for the wild type protein at this temperature (Ulbrichova et al. 2009). Based on the collective evidence, the p.Asp178Asn variant is considered to be a variant of unknown significance, but suspicious for pathogenicity for hydroxymethylbilane synthase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Acute Intermittent Porphyria
(Autosomal dominant inheritance)
Affected status: not applicable
Allele origin:
not applicable
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Mount Sinai Diagnostic Laboratory, Icahn School of Medicine at Mount Sinai
Accession: SCV001132053.1
First in ClinVar: Jan 02, 2020 Last updated: Jan 02, 2020 |
Result:
p.D178N has been described with a decrease (~50%) in erythrocyte HMBS activity and a frequency of ~0.0006, documenting its pathogenicity (B. Chen, et al., Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease. Hum Mutat 37:1215-1222, 2016).
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Acute intermittent porphyria
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002516546.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Uncertain significance
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Acute intermittent porphyria
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769000.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with acute intermittent porphyria (MIM#176000). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Individuals heterozygous for a pathogenic HMBS variant are at risk of developing symptoms, however most never have symptoms (PMID: 20301372). In susceptible HMBS variant carriers, triggering factors included hormonal changes and commonly used drugs (PMID: 33445488). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (76 heterozygotes, 1 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated dipyromethane cofactor binding domain (UniProt). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Asp178His) variant has been reported in cis with a p.(Arg173Gly) variant in an individual with acute intermittent porphyria (AIP). Prokaryotic expression study showed mutant enzyme with D178H had significant residual activity, while R173G and R173G+D178H mutant enzymes had no residual activity. (PMID: 19656452) (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as uncertain significance and likely pathogenic in ClinVar. It has also been reported in multiple unrelated individuals with AIP, however some of them had borderline or normal levels of urinary ALA and PBG. Most of these reports studied European patient cohorts (PMIDs: 9199558, 9350165, 19138865, 19401933). (I) 1010 - Functional evidence for this variant is inconclusive. Reduced erythrocyte HMBS activity has been reported in symptomatic individual and her asymptomatic mother who were heterozygous for this variant, however both exhibited borderline levels of urinary ALA and PBG (PMID: 19138865). Functional studies in E.coli showed high residual HMBS activity of 81% of the wildtype and a reduction in enzyme thermostability (PMIDs: 19138865, 31073229). (SP) 1205 - This variant has been shown to be maternally inherited (by quad analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(Oct 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002164315.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 178 of the HMBS protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 178 of the HMBS protein (p.Asp178Asn). This variant is present in population databases (rs536814318, gnomAD 0.3%). This missense change has been observed in individual(s) with HMBS-related disease (PMID: 9199558, 19267997). ClinVar contains an entry for this variant (Variation ID: 372379). 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 not expected to disrupt HMBS protein function. Experimental studies have shown that this missense change affects HMBS function (PMID: 19138865). 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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Likely pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Acute intermittent porphyria
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002016601.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Acute intermittent porphyria
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005042966.2
First in ClinVar: May 12, 2024 Last updated: Jul 15, 2024 |
Comment:
The observed missense variant c.532G>A (p.Asp178Asn) in HMBS gene has been reported previously in heterozygous state in an individual affected with acute intermittent porphyria. (Ulbrichova … (more)
The observed missense variant c.532G>A (p.Asp178Asn) in HMBS gene has been reported previously in heterozygous state in an individual affected with acute intermittent porphyria. (Ulbrichova D et al. 2009). In vitro studies shows conflicting evidence with this variant leading to only a slightly reduced (~81% of the wild-type) enzyme activity, with a shift in its optimal pH and was thermo labile (Ulbrichova et al., 2009). The p.Asp178Asn variant is present with an allele frequency of 0.05% (78 heterozygotes and 1 homozygote) in the gnomAD exomes database. This variant has been submitted to the ClinVar as Uncertain significance / Likely pathogenic / Pathogenic. The amino acid change p.Asp178Asn in HMBS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 178 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. However, since this variant has also been reported in asymptomatic individuals with a reduced enzymatic activity (Nordmann et al. 1997; Ulbrichova D et al. 2009); this variant has been classified as a Variant of Uncertain Significance (VUS). (less)
Clinical Features:
Abnormality of the nervous system (present)
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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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Acute Intermittent Porphyria. | Adam MP | - | 2024 | PMID: 20301372 |
Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators. | Bustad HJ | International journal of molecular sciences | 2021 | PMID: 33445488 |
International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias. | Chen B | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31073229 |
Identification and characterization of HMBS gene mutations in Spanish patients with acute intermittent porphyria. | Méndez M | Cellular and molecular biology (Noisy-le-Grand, France) | 2009 | PMID: 19656452 |
Clinical aspects of acute intermittent porphyria in northern Sweden: a population-based study. | Bylesjö I | Scandinavian journal of clinical and laboratory investigation | 2009 | PMID: 19401933 |
Awareness is the name of the game: clinical and biochemical evaluation of a case of a girl diagnosed with acute intermittent porphyria associated with autism. | Luder AS | Cellular and molecular biology (Noisy-le-Grand, France) | 2009 | PMID: 19267997 |
Correlation between biochemical findings, structural and enzymatic abnormalities in mutated HMBS identified in six Israeli families with acute intermittent porphyria. | Ulbrichova D | Blood cells, molecules & diseases | 2009 | PMID: 19138865 |
Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene. | Floderus Y | Clinical genetics | 2002 | PMID: 12372055 |
Acute intermittent porphyria: prevalence of mutations in the porphobilinogen deaminase gene in blood donors in France. | Nordmann Y | Journal of internal medicine | 1997 | PMID: 9350165 |
Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria. | Puy H | American journal of human genetics | 1997 | PMID: 9199558 |
Text-mined citations for rs536814318 ...
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.