ClinVar Genomic variation as it relates to human health
NM_000282.4(PCCA):c.229C>T (p.Arg77Trp)
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.229C>T (p.Arg77Trp)
Variation ID: 550747 Accession: VCV000550747.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q32.3 13: 100111886 (GRCh38) [ NCBI UCSC ] 13: 100764140 (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 5, 2018 Feb 14, 2024 Dec 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000282.4:c.229C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000273.2:p.Arg77Trp missense NM_001127692.3:c.151C>T NP_001121164.1:p.Arg51Trp missense NM_001178004.2:c.229C>T NP_001171475.1:p.Arg77Trp missense NM_001352605.2:c.229C>T NP_001339534.1:p.Arg77Trp missense NM_001352606.2:c.229C>T NP_001339535.1:p.Arg77Trp missense NM_001352607.2:c.151C>T NP_001339536.1:p.Arg51Trp missense NM_001352608.2:c.151C>T NP_001339537.1:p.Arg51Trp missense NM_001352609.2:c.229C>T NP_001339538.1:p.Arg77Trp missense NM_001352610.2:c.-638C>T 5 prime UTR NM_001352611.2:c.-638C>T 5 prime UTR NM_001352612.2:c.-638C>T 5 prime UTR NR_148027.2:n.257C>T non-coding transcript variant NR_148028.2:n.257C>T non-coding transcript variant NR_148029.2:n.179C>T non-coding transcript variant NR_148030.2:n.257C>T non-coding transcript variant NR_148031.2:n.257C>T non-coding transcript variant NC_000013.11:g.100111886C>T NC_000013.10:g.100764140C>T NG_008768.1:g.27804C>T - Protein change
- R77W, R51W
- Other names
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- Canonical SPDI
- NC_000013.11:100111885: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.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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 | ||
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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
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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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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 27, 2023 | RCV000665579.10 |
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
(Feb 15, 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: SCV000789725.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Nov 29, 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: SCV000919957.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: PCCA c.229C>T (p.Arg77Trp) results in a non-conservative amino acid change located in the Biotin carboxylation domain & Biotin carboxylase-like, N-terminal domain of the … (more)
Variant summary: PCCA c.229C>T (p.Arg77Trp) results in a non-conservative amino acid change located in the Biotin carboxylation domain & Biotin carboxylase-like, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 245438 control chromosomes (gnomAD). c.229C>T has been reported in the literature in individuals affected with Propionic Acidemia (Chiu_2014, Perez_2010, Yang_2004, Perez-Cerda_2000). These data indicate that the variant is likely to be associated with disease. Experimental evidence reported in a publication evaluating an impact on protein function (Clavero_2002) demonstrated the variant to clearly diminish PCC activity (<10% of normal activity). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 19, 2022)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002798131.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 11, 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: SCV004202842.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 27, 2023)
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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: SCV001580695.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 77 of the PCCA protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 77 of the PCCA protein (p.Arg77Trp). This variant is present in population databases (rs141371306, gnomAD 0.02%). This missense change has been observed in individual(s) with propionic acidemia (PMID: 10780784, 15059621, 20549364, 24863100). This variant is also known as 154C>T (R52W). ClinVar contains an entry for this variant (Variation ID: 550747). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PCCA function (PMID: 12385775). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 28, 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: SCV002094957.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Two frequent mutations associated with the classic form of propionic acidemia in Taiwan. | Chiu YH | Biochemical genetics | 2014 | PMID: 24863100 |
Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase. | Huang CS | Nature | 2010 | PMID: 20725044 |
The molecular landscape of propionic acidemia and methylmalonic aciduria in Latin America. | Pérez B | Journal of inherited metabolic disease | 2010 | PMID: 20549364 |
Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia. | Yang X | Molecular genetics and metabolism | 2004 | PMID: 15059621 |
Functional characterization of PCCA mutations causing propionic acidemia. | Clavero S | Biochimica et biophysica acta | 2002 | PMID: 12385775 |
Potential relationship between genotype and clinical outcome in propionic acidaemia patients. | Pérez-Cerdá C | European journal of human genetics : EJHG | 2000 | PMID: 10780784 |
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 |
Text-mined citations for rs141371306 ...
HelpRecord last updated Feb 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.