ClinVar Genomic variation as it relates to human health
NM_000282.4(PCCA):c.937C>T (p.Arg313Ter)
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_000282.4(PCCA):c.937C>T (p.Arg313Ter)
Variation ID: 38870 Accession: VCV000038870.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q32.3 13: 100273218 (GRCh38) [ NCBI UCSC ] 13: 100925472 (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 Apr 4, 2013 Feb 14, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000282.4:c.937C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000273.2:p.Arg313Ter nonsense NM_001127692.3:c.859C>T NP_001121164.1:p.Arg287Ter nonsense NM_001178004.2:c.937C>T NP_001171475.1:p.Arg313Ter nonsense NM_001352605.2:c.937C>T NP_001339534.1:p.Arg313Ter nonsense NM_001352606.2:c.937C>T NP_001339535.1:p.Arg313Ter nonsense NM_001352607.2:c.859C>T NP_001339536.1:p.Arg287Ter nonsense NM_001352608.2:c.859C>T NP_001339537.1:p.Arg287Ter nonsense NM_001352609.2:c.937C>T NP_001339538.1:p.Arg313Ter nonsense NM_001352610.2:c.-9C>T 5 prime UTR NM_001352611.2:c.-9C>T 5 prime UTR NM_001352612.2:c.-9C>T 5 prime UTR NR_148027.2:n.965C>T non-coding transcript variant NR_148028.2:n.965C>T non-coding transcript variant NR_148029.2:n.887C>T non-coding transcript variant NR_148030.2:n.965C>T non-coding transcript variant NR_148031.2:n.965C>T non-coding transcript variant NC_000013.11:g.100273218C>T NC_000013.10:g.100925472C>T NG_008768.1:g.189136C>T - Protein change
- R313*, R287*
- Other names
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- Canonical SPDI
- NC_000013.11:100273217: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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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PCCA | - | - |
GRCh38 GRCh37 |
1335 | 1455 |
Conditions - Germline
Condition
Help
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
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
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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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Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2024 | RCV000032113.25 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 3, 2013 | RCV000790683.4 |
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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Pathogenic
(Oct 25, 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: SCV004202835.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 28, 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: SCV000959042.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg313*) in the PCCA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg313*) in the PCCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCCA are known to be pathogenic (PMID: 15464417). This variant is present in population databases (rs138149179, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with PCCA-related conditions (PMID: 9887338, 10101253, 22033733, 27227689). ClinVar contains an entry for this variant (Variation ID: 38870). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2012)
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criteria provided, single submitter
Method: research
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Propionic Acidemia
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Study: ORGANIC ACIDURIAS
Accession: SCV000256838.1 First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016
Comment:
Nonsense mutation
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Number of individuals with the variant: 3
Age: 0-30 days
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Pathogenic
(Jun 27, 2017)
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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: SCV000792407.1
First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016 |
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Pathogenic
(May 25, 2018)
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criteria provided, single submitter
Method: clinical testing
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Propionyl-CoA carboxylase deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919956.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: PCCA c.937C>T (p.Arg313X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: PCCA c.937C>T (p.Arg313X) 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 3.2e-05 in 276992 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PCCA causing Propionic Acidemia (3.2e-05 vs 3.40e-03), allowing no conclusion about variant significance. The variant, c.937C>T, has been reported in the literature in multiple individuals affected with Propionic Acidemia (Kraus_2012, Gupta_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, with complete absence of PCCA and very low levels of PCCB in a cultured liver cells homozygous for this variant (Chapman_PCCA_HMG_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Propionic acidemia
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318797.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 27227689, 22033733). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 27227689, 22033733). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000397). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Acidosis (present) , Failure to thrive (present) , Hyperammonemia (present) , Hyperglycinemia (present)
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Pathogenic
(Jun 04, 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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Revvity Omics, Revvity
Accession: SCV002016539.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 03, 2013)
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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: SCV000225504.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Propionic acidemia
(Autosomal recessive 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: SCV002767187.1
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 Pathogenic. 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 Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with propionicacidemia (MIM#606054). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously described as pathogenic in multiple individuals with propionic acidaemia (ClinVar, PMID: 32819290, 27227689, 22033733). (SP) 1206 - This variant has been shown to be paternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Dec 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Propionic acidemia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002818470.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
A heterozygous single base pair deletion in exon 12 of the PCCA gene that results in a frameshift and premature truncation of the amino acids … (more)
A heterozygous single base pair deletion in exon 12 of the PCCA gene that results in a frameshift and premature truncation of the amino acids downstream to codon 313 (p.Arg313Ter) was detected. This variant has not been reported in the 1000 genomes, gnomAD and our internal databases. The in silico predictions of the variant is damaging by dbSNP and clinvar databases. The reference region is conserved across species. In summary, the variant is pathogenic. (less)
Age: 20-29 years
Sex: female
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Dec 31, 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: SCV002094972.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Propionic acidemia
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000055653.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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A novel delins (c.773_819+47delinsAA) mutation of the PCCA gene associated with neonatal-onset propionic acidemia: a case report. | Wang HR | BMC medical genetics | 2020 | PMID: 32819290 |
Seventeen Novel Mutations in PCCA and PCCB Genes in Indian Propionic Acidemia Patients, and Their Outcomes. | Gupta D | Genetic testing and molecular biomarkers | 2016 | PMID: 27227689 |
Recapitulation of metabolic defects in a model of propionic acidemia using patient-derived primary hepatocytes. | Chapman KA | Molecular genetics and metabolism | 2016 | PMID: 26740382 |
Propionic Acidemia. | Adam MP | - | 2016 | PMID: 22593918 |
Feasibility of nonsense mutation readthrough as a novel therapeutical approach in propionic acidemia. | Sánchez-Alcudia R | Human mutation | 2012 | PMID: 22334403 |
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 |
Genetic heterogeneity in propionic acidemia patients with alpha-subunit defects. Identification of five novel mutations, one of them causing instability of the protein. | Richard E | Biochimica et biophysica acta | 1999 | PMID: 10101253 |
Detection of a normally rare transcript in propionic acidemia patients with mRNA destabilizing mutations in the PCCA gene. | Campeau E | Human molecular genetics | 1999 | PMID: 9887338 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PCCA | - | - | - | - |
Text-mined citations for rs138149179 ...
HelpRecord last updated May 08, 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.