PP3, PP4, PM2, PM5, PS4
ClinVar Genomic variation as it relates to human health
NM_000190.4(HMBS):c.76C>T (p.Arg26Cys)
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.
(4)
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.
Pathogenic/Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000190.4(HMBS):c.76C>T (p.Arg26Cys)
Variation ID: 645443 Accession: VCV000645443.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.3 11: 119088297 (GRCh38) [ NCBI UCSC ] 11: 118959007 (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 14, 2019 Apr 6, 2024 Mar 29, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000190.4:c.76C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000181.2:p.Arg26Cys missense NM_001024382.2:c.25C>T NP_001019553.1:p.Arg9Cys missense NM_001258208.2:c.76C>T NP_001245137.1:p.Arg26Cys missense NM_001258209.2:c.25C>T NP_001245138.1:p.Arg9Cys missense NC_000011.10:g.119088297C>T NC_000011.9:g.118959007C>T NG_008093.1:g.8421C>T LRG_1076:g.8421C>T LRG_1076t1:c.76C>T LRG_1076p1:p.Arg26Cys LRG_1076t2:c.25C>T LRG_1076p2:p.Arg9Cys - Protein change
- R26C, R9C
- Other names
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p.Arg26Cys
- Canonical SPDI
- NC_000011.10:119088296: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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. |
|||
| HMBS | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
590 | 636 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 6, 2023 | RCV000799514.14 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 29, 2024 | RCV003152734.3 |
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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|---|---|---|---|---|---|
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Pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002525805.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
PP3, PP4, PM2, PM5, PS4
|
|
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Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Acute intermittent porphyria
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841778.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide strong evidence of the … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11055586, 16025832). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000645443) and different missense changes at the same codon (p.Arg26His, p.Arg26Leu / ClinVar ID: VCV000001443, VCV000665873) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Gastritis (present) , Myopia (present)
|
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Pathogenic
(Jul 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000939179.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
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) … (more)
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 HMBS protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg26 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8401516, 9238757, 9281416, 18627369, 19292878, 19656452, 20978940). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HMBS function (PMID: 11055586, 19292878). ClinVar contains an entry for this variant (Variation ID: 645443). This missense change has been observed in individuals with acute intermittent porphyria (PMID: 7757070, 9199558, 10502788, 11831862, 16817012, 18627369, 19292878, 20978940, 24997713). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 26 of the HMBS protein (p.Arg26Cys). (less)
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Likely pathogenic
(Mar 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Acute intermittent porphyria
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807659.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
Comment:
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11055586, 16025832). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000645443) and different missense changes at the same codon (p.Arg26His, p.Arg26Leu / ClinVar ID: VCV000001443, VCV000665873) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
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 HMBS protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg26 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8401516, 9238757, 9281416, 18627369, 19292878, 19656452, 20978940). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HMBS function (PMID: 11055586, 19292878). ClinVar contains an entry for this variant (Variation ID: 645443). This missense change has been observed in individuals with acute intermittent porphyria (PMID: 7757070, 9199558, 10502788, 11831862, 16817012, 18627369, 19292878, 20978940, 24997713). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 26 of the HMBS protein (p.Arg26Cys).
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:
PP3, PP4, PM2, PM5, PS4
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11055586, 16025832). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000645443) and different missense changes at the same codon (p.Arg26His, p.Arg26Leu / ClinVar ID: VCV000001443, VCV000665873) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
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 HMBS protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg26 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8401516, 9238757, 9281416, 18627369, 19292878, 19656452, 20978940). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HMBS function (PMID: 11055586, 19292878). ClinVar contains an entry for this variant (Variation ID: 645443). This missense change has been observed in individuals with acute intermittent porphyria (PMID: 7757070, 9199558, 10502788, 11831862, 16817012, 18627369, 19292878, 20978940, 24997713). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 26 of the HMBS protein (p.Arg26Cys).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Seven Novel Mutations in Bulgarian Patients with Acute Hepatic Porphyrias (AHP). | Dragneva S | JIMD reports | 2014 | PMID: 24997713 |
| Marked geographic aggregation of acute intermittent porphyria families carrying mutation Q180X in Venezuelan populations, with description of further mutations. | Paradisi I | Journal of inherited metabolic disease | 2010 | PMID: 20978940 |
| 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 |
| Acute intermittent porphyria--impact of mutations found in the hydroxymethylbilane synthase gene on biochemical and enzymatic protein properties. | Ulbrichova D | The FEBS journal | 2009 | PMID: 19292878 |
| HMBS mutations in Chinese patients with acute intermittent porphyria. | Yang CC | Annals of human genetics | 2008 | PMID: 18627369 |
| Genetic and biochemical characterization of 16 acute intermittent porphyria cases with a high prevalence of the R173W mutation. | To-Figueras J | Journal of inherited metabolic disease | 2006 | PMID: 16817012 |
| Characterization of two isoalleles and three mutations in both isoforms of purified recombinant human porphobilinogen deaminase. | Brøns-Poulsen J | Scandinavian journal of clinical and laboratory investigation | 2005 | PMID: 16025832 |
| Acute intermittent porphyria: heterogeneity of mutations in the hydroxymethylbilane synthase gene in Italy. | Martinez di Montemuros F | Blood cells, molecules & diseases | 2001 | PMID: 11831862 |
| Acute intermittent porphyria: expression of mutant and wild-type porphobilinogen deaminase in COS-1 cells. | Mustajoki S | Molecular medicine (Cambridge, Mass.) | 2000 | PMID: 11055586 |
| Acute intermittent porphyria: characterization of two novel mutations in the porphobilinogen deaminase gene, one amino acid deletion (453-455delAGC) and one splicing aceptor site mutation (IVS8-1G>T). | De Siervi A | Human mutation | 1999 | PMID: 10502788 |
| Acute intermittent porphyria: the in vitro expression of mutant hydroxymethylbilane synthase. | Ong PM | Molecular and cellular probes | 1997 | PMID: 9281416 |
| Molecular analysis of porphobilinogen (PBG) deaminase gene mutations in acute intermittent porphyria: first study in patients of Slavic origin. | Rosipal R | Scandinavian journal of clinical and laboratory investigation | 1997 | PMID: 9238757 |
| Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria. | Puy H | American journal of human genetics | 1997 | PMID: 9199558 |
| Acute intermittent porphyria in Finland: 19 mutations in the porphobilinogen deaminase gene. | Kauppinen R | Human molecular genetics | 1995 | PMID: 7757070 |
| Acute intermittent porphyria caused by an arginine to histidine substitution (R26H) in the cofactor-binding cleft of porphobilinogen deaminase. | Llewellyn DH | Human molecular genetics | 1993 | PMID: 8401516 |
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Text-mined citations for rs998842815 ...
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.