ClinVar Genomic variation as it relates to human health
NM_000532.5(PCCB):c.942C>A (p.Tyr314Ter)
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_000532.5(PCCB):c.942C>A (p.Tyr314Ter)
Variation ID: 203882 Accession: VCV000203882.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q22.3 3: 136301087 (GRCh38) [ NCBI UCSC ] 3: 136019929 (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 Dec 6, 2016 Feb 14, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000532.5:c.942C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000523.2:p.Tyr314Ter nonsense NM_001178014.2:c.1002C>A NP_001171485.1:p.Tyr334Ter nonsense NC_000003.12:g.136301087C>A NC_000003.11:g.136019929C>A NG_008939.1:g.55763C>A - Protein change
- Y314*, Y334*
- Other names
- p.Y314*:TAC>TAA
- Canonical SPDI
- NC_000003.12:136301086:C: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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
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. |
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PCCB | - | - |
GRCh38 GRCh37 |
1147 | 1172 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Oct 11, 2016 | RCV000186088.6 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000341685.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2021 | RCV002517828.1 |
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. |
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Likely pathogenic
(Jun 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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Propionic acidemia
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800299.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(Jan 05, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000338743.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Oct 11, 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: SCV000239112.7
First in ClinVar: Jul 18, 2015 Last updated: Dec 06, 2016 |
Comment:
The Y314X nonsense variant in the PCCB gene has been reported previously in association with propionic acidemia (Lévesque et al. 2012). The Y314X variant was … (more)
The Y314X nonsense variant in the PCCB gene has been reported previously in association with propionic acidemia (Lévesque et al. 2012). The Y314X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret Y314X to be a pathogenic variant. (less)
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Pathogenic
(Jun 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Propionic acidemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360762.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PCCB c.942C>A (p.Tyr314X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: PCCB c.942C>A (p.Tyr314X) 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 1.2e-05 in 251454 control chromosomes (gnomAD). The variant, c.942C>A, has been reported in the literature in individuals affected with Propionic Acidemia (Levesque_2011, Sanchez-Alcudia_2012). These data indicate that the variant may be associated with disease. At least one publication, Sanchez-Alcudia_2012, reports PCC activity of this variant from patients fibroblasts treated with readthrough drugs was <10% of normal activity. Three ClinVar submissions from clinical diagnostic laboratories (last evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003571171.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.942C>A (p.Y314*) alteration, located in exon 9 (coding exon 9) of the PCCB gene, consists of a C to A substitution at nucleotide position … (more)
The c.942C>A (p.Y314*) alteration, located in exon 9 (coding exon 9) of the PCCB gene, consists of a C to A substitution at nucleotide position 942. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 314. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the PCCB c.942C>A alteration was observed in 0.0012% (3/251,454) of total alleles studied, with a frequency of 0.0026% (3/113,742) in the European (non-Finnish) subpopulation. This alteration has been identified with a second mutation in PCCB in an individual with biochemically confirmed propionic aciduria (Levesque, 2012). Based on the available evidence, this alteration is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Propionic acidemia
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004205194.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jun 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Propionic acidemia
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003824765.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Propionic acidemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001205750.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr314*) 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.Tyr314*) 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 (rs572246667, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with propionic aciduria (PMID: 23430860). ClinVar contains an entry for this variant (Variation ID: 203882). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Propionic acidemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454522.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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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 |
Feasibility of nonsense mutation readthrough as a novel therapeutical approach in propionic acidemia. | Sánchez-Alcudia R | Human mutation | 2012 | PMID: 22334403 |
Propionic acidemia: mutation update and functional and structural effects of the variant alleles. | Desviat LR | Molecular genetics and metabolism | 2004 | PMID: 15464417 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PCCB | - | - | - | - |
Text-mined citations for rs572246667 ...
HelpRecord last updated Mar 17, 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.