This sequence change creates a premature translational stop signal (p.Glu331*) in the PCCB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCCB are known to be pathogenic (PMID: 15464417). This variant is present in population databases (rs763069936, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with propionic aciduria (PMID: 12559849, 22033733, 23430860, 24516753). ClinVar contains an entry for this variant (Variation ID: 167423). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000532.5(PCCB):c.990dup (p.Glu331Ter)
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.
(14)
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
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000532.5(PCCB):c.990dup (p.Glu331Ter)
Variation ID: 167423 Accession: VCV000167423.39
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 3q22.3 3: 136316958-136316959 (GRCh38) [ NCBI UCSC ] 3: 136035800-136035801 (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 Jun 28, 2015 Oct 13, 2024 Sep 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000532.5:c.990dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000523.2:p.Glu331Ter nonsense NM_000532.5:c.990dupT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000532.4:c.990dup NM_001178014.2:c.1050dup NP_001171485.1:p.Glu351Ter nonsense NC_000003.12:g.136316964dup NC_000003.11:g.136035806dup NG_008939.1:g.71640dup - Protein change
- E351*, E331*
- Other names
- -
- Canonical SPDI
- NC_000003.12:136316958:TTTTTT:TTTTTTT
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| PCCB | - | - |
GRCh38 GRCh37 |
1174 | 1199 | |
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
|
Feb 18, 2020 | RCV000153647.15 | |
|
PCCB-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Aug 23, 2024 | RCV004752762.1 |
| Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
|
Sep 22, 2024 | RCV000173704.22 |
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
(Mar 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001162959.2
First in ClinVar: Mar 01, 2020 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000631920.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu331*) in the PCCB gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu331*) in the PCCB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCCB are known to be pathogenic (PMID: 15464417). This variant is present in population databases (rs763069936, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with propionic aciduria (PMID: 12559849, 22033733, 23430860, 24516753). ClinVar contains an entry for this variant (Variation ID: 167423). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811715.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Sep 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005374450.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
|
|
|
Pathogenic
(Mar 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000700506.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
PROPIONIC ACIDEMIA
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046091.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This nonsense variant found in exon 11 of 16 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated … (more)
This nonsense variant found in exon 11 of 16 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as both a compound heterozygous and homozygous change in patients with propionic acidemia (MIM#: 606054; PMID: 12559849, 22033733, 23430860, 24516753). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (25/282848) and thus is presumed to be rare. Based on the available evidence, the c.1050dup (p.Glu351Ter) variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jul 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697273.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The PCCB c.990dupT (p.Glu331X) variant results in a premature termination codon, predicted to cause a truncated or absent PCCB protein due to nonsense … (more)
Variant summary: The PCCB c.990dupT (p.Glu331X) variant results in a premature termination codon, predicted to cause a truncated or absent PCCB protein due to nonsense mediated decay, which are commonly known mechanisms for disease.This variant was found in 6/121406 control chromosomes at a frequency of 0.0000494, which does not exceed the estimated maximal expected allele frequency of a pathogenic PCCB variant (0.0025). Multiple publications have cited the variant in affected compound heterozygote and homozygote individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
inherited
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002097857.1 First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022 |
Clinical Features:
Seizure (present)
Secondary finding: no
|
|
|
Pathogenic
(Feb 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000239123.10
First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22033733, 24516753, 24059531, 23430860, 20549364, 12559849, 30705822, 31916709) (less)
|
|
|
Pathogenic
(Apr 01, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Propionic acidemia
Affected status: yes
Allele origin:
germline
|
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927927.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
|
|
|
Pathogenic
(Dec 27, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132452.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001454523.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Jan 29, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Propionic acidemia
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001132883.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
|
|
|
Pathogenic
(Aug 23, 2024)
|
no assertion criteria provided
Method: clinical testing
|
PCCB-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005360574.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The PCCB c.990dupT variant is predicted to result in premature protein termination (p.Glu331*). This variant has been reported in the compound heterozygous state with a … (more)
The PCCB c.990dupT variant is predicted to result in premature protein termination (p.Glu331*). This variant has been reported in the compound heterozygous state with a second pathogenic variant or in the homozygous state in unrelated individuals with propionic acidemia (Pérez et al. 2003. PubMed ID: 12559849; Ali et al. 2011. PubMed ID: 21483992; Al-Hamed et al. 2019. PubMed ID: 30705822). Analysis of propionyl-CoA carboxylase (PCC) activity in skin fibroblasts from a patient who was compound heterozygous for this variant and a second pathogenic variant (c.1228C>T, p.Arg410Trp) revealed that together, these two variants nearly abolished the enzyme activity (Pérez-Cerdá et al. 2003. PubMed ID: 12757933). This variant is reported in 0.10% of alleles in individuals of African descent in gnomAD. Nonsense variants in PCCB are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This nonsense variant found in exon 11 of 16 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as both a compound heterozygous and homozygous change in patients with propionic acidemia (MIM#: 606054; PMID: 12559849, 22033733, 23430860, 24516753). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (25/282848) and thus is presumed to be rare. Based on the available evidence, the c.1050dup (p.Glu351Ter) variant is classified as Pathogenic.
Comment:
Variant summary: The PCCB c.990dupT (p.Glu331X) variant results in a premature termination codon, predicted to cause a truncated or absent PCCB protein due to nonsense mediated decay, which are commonly known mechanisms for disease.This variant was found in 6/121406 control chromosomes at a frequency of 0.0000494, which does not exceed the estimated maximal expected allele frequency of a pathogenic PCCB variant (0.0025). Multiple publications have cited the variant in affected compound heterozygote and homozygote individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22033733, 24516753, 24059531, 23430860, 20549364, 12559849, 30705822, 31916709)
Comment:
The PCCB c.990dupT variant is predicted to result in premature protein termination (p.Glu331*). This variant has been reported in the compound heterozygous state with a second pathogenic variant or in the homozygous state in unrelated individuals with propionic acidemia (Pérez et al. 2003. PubMed ID: 12559849; Ali et al. 2011. PubMed ID: 21483992; Al-Hamed et al. 2019. PubMed ID: 30705822). Analysis of propionyl-CoA carboxylase (PCC) activity in skin fibroblasts from a patient who was compound heterozygous for this variant and a second pathogenic variant (c.1228C>T, p.Arg410Trp) revealed that together, these two variants nearly abolished the enzyme activity (Pérez-Cerdá et al. 2003. PubMed ID: 12757933). This variant is reported in 0.10% of alleles in individuals of African descent in gnomAD. Nonsense variants in PCCB are expected to be pathogenic. This variant is interpreted as 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:
This sequence change creates a premature translational stop signal (p.Glu331*) in the PCCB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCCB are known to be pathogenic (PMID: 15464417). This variant is present in population databases (rs763069936, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with propionic aciduria (PMID: 12559849, 22033733, 23430860, 24516753). ClinVar contains an entry for this variant (Variation ID: 167423). For these reasons, this variant has been classified as Pathogenic.
Comment:
This nonsense variant found in exon 11 of 16 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as both a compound heterozygous and homozygous change in patients with propionic acidemia (MIM#: 606054; PMID: 12559849, 22033733, 23430860, 24516753). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (25/282848) and thus is presumed to be rare. Based on the available evidence, the c.1050dup (p.Glu351Ter) variant is classified as Pathogenic.
Comment:
Variant summary: The PCCB c.990dupT (p.Glu331X) variant results in a premature termination codon, predicted to cause a truncated or absent PCCB protein due to nonsense mediated decay, which are commonly known mechanisms for disease.This variant was found in 6/121406 control chromosomes at a frequency of 0.0000494, which does not exceed the estimated maximal expected allele frequency of a pathogenic PCCB variant (0.0025). Multiple publications have cited the variant in affected compound heterozygote and homozygote individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22033733, 24516753, 24059531, 23430860, 20549364, 12559849, 30705822, 31916709)
Comment:
The PCCB c.990dupT variant is predicted to result in premature protein termination (p.Glu331*). This variant has been reported in the compound heterozygous state with a second pathogenic variant or in the homozygous state in unrelated individuals with propionic acidemia (Pérez et al. 2003. PubMed ID: 12559849; Ali et al. 2011. PubMed ID: 21483992; Al-Hamed et al. 2019. PubMed ID: 30705822). Analysis of propionyl-CoA carboxylase (PCC) activity in skin fibroblasts from a patient who was compound heterozygous for this variant and a second pathogenic variant (c.1228C>T, p.Arg410Trp) revealed that together, these two variants nearly abolished the enzyme activity (Pérez-Cerdá et al. 2003. PubMed ID: 12757933). This variant is reported in 0.10% of alleles in individuals of African descent in gnomAD. Nonsense variants in PCCB are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutation Spectrum and Birth Prevalence of Inborn Errors of Metabolism among Emiratis: A study from Tawam Hospital Metabolic Center, United Arab Emirates. | Al-Shamsi A | Sultan Qaboos University medical journal | 2014 | PMID: 24516753 |
| Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. | Nizon M | Orphanet journal of rare diseases | 2013 | PMID: 24059531 |
| Short-term outcome of propionic aciduria treated at presentation with N-carbamylglutamate: a retrospective review of four patients. | Lévesque S | JIMD reports | 2012 | PMID: 23430860 |
| Mutation analysis in 54 propionic acidemia patients. | Kraus JP | Journal of inherited metabolic disease | 2012 | PMID: 22033733 |
| Propionic acidemia: mutation update and functional and structural effects of the variant alleles. | Desviat LR | Molecular genetics and metabolism | 2004 | PMID: 15464417 |
| Propionic acidemia: identification of twenty-four novel mutations in Europe and North America. | Pérez B | Molecular genetics and metabolism | 2003 | PMID: 12559849 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PCCB | - | - | - | - |
Text-mined citations for rs786200983 ...
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 Oct 20, 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.