This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 668 of the PCCA protein (p.Gly668Arg). This variant is present in population databases (rs771438170, gnomAD 0.01%). This missense change has been observed in individuals with propionic acidemia (PMID: 10329019, 19099776, 27227689, 29978829). ClinVar contains an entry for this variant (Variation ID: 218266). 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 PCCA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PCCA function (PMID: 10329019, 12385775). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000282.4(PCCA):c.2002G>A (p.Gly668Arg)
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000282.4(PCCA):c.2002G>A (p.Gly668Arg)
Variation ID: 218266 Accession: VCV000218266.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q32.3 13: 100515529 (GRCh38) [ NCBI UCSC ] 13: 101167783 (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 Jul 24, 2016 Nov 17, 2024 Feb 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000282.4:c.2002G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000273.2:p.Gly668Arg missense NM_001127692.3:c.1924G>A NP_001121164.1:p.Gly642Arg missense NM_001178004.2:c.1900-12146G>A intron variant NM_001352605.2:c.1948G>A NP_001339534.1:p.Gly650Arg missense NM_001352606.2:c.1858G>A NP_001339535.1:p.Gly620Arg missense NM_001352607.2:c.1822-12146G>A intron variant NM_001352608.2:c.1780G>A NP_001339537.1:p.Gly594Arg missense NM_001352610.2:c.1057G>A NP_001339539.1:p.Gly353Arg missense NM_001352611.2:c.1003G>A NP_001339540.1:p.Gly335Arg missense NM_001352612.2:c.913G>A NP_001339541.1:p.Gly305Arg missense NR_148028.2:n.2011G>A non-coding transcript variant NR_148029.2:n.1933G>A non-coding transcript variant NR_148030.2:n.2114G>A non-coding transcript variant NR_148031.2:n.1927G>A non-coding transcript variant NC_000013.11:g.100515529G>A NC_000013.10:g.101167783G>A NG_008768.1:g.431447G>A P05165:p.Gly668Arg - Protein change
- G668R, G594R, G335R, G650R, G353R, G620R, G642R, G305R
- Other names
- -
- Canonical SPDI
- NC_000013.11:100515528:G:A
-
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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- 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. |
|||
| PCCA | - | - |
GRCh38 GRCh37 |
1370 | 1491 | |
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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 21, 2023 | RCV000235940.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 1, 2024 | RCV003884401.8 |
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
(Jan 01, 2014)
|
criteria provided, single submitter
Method: research
|
Propionic Acidemia
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Study: ORGANIC ACIDURIAS
Accession: SCV000256857.1 First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016
Comment:
Missense mutation
|
Number of individuals with the variant: 1
Age: 0-30 days
|
|
|
Likely pathogenic
(May 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000791909.1
First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016 |
|
|
|
Pathogenic
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001398286.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 668 of the PCCA protein (p.Gly668Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 668 of the PCCA protein (p.Gly668Arg). This variant is present in population databases (rs771438170, gnomAD 0.01%). This missense change has been observed in individuals with propionic acidemia (PMID: 10329019, 19099776, 27227689, 29978829). ClinVar contains an entry for this variant (Variation ID: 218266). 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 PCCA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PCCA function (PMID: 10329019, 12385775). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Dec 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202839.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004702604.8
First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024 |
Comment:
PCCA: PM3:Very Strong, PM2, PS3:Supporting
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Accession: SCV005397303.1
First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024 |
Comment:
This sequence variant is a single nucleotide substitution (G>A) at coding position 2002 of the PCCA gene that results in a glycine to arginine amino … (more)
This sequence variant is a single nucleotide substitution (G>A) at coding position 2002 of the PCCA gene that results in a glycine to arginine amino acid change at residue 668 of the PCCA protein. The Gly668 residue falls in the biotin carboxyl carrier protein domain which is critical to PCCA's role in the biotinylation and catabolism of certain amino acids (PMID: 20725044). This is a previously reported variant (ClinVar) that has been observed in individuals affected by propionic acidemia (PMID: 10329019, 27227689, 29978829). This variant is present in 3 of 251,414 alleles (0.001%) in the gnomAD population database. Multiple bioinformatic tools predict that this glycine to arginine amino acid change would be damaging, and the glycine residue is strongly conserved at this position across the vertebrate species examined. Functiol studies have observed that this variant abolishes the biotinylating activity of the protein resulting from this variant (PMID: 10329019, 12385775). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM2, PP3, PS3 (less)
|
|
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Pathogenic
(Jun 30, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002094987.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
PCCA: PM3:Very Strong, PM2, PS3:Supporting
Comment:
This sequence variant is a single nucleotide substitution (G>A) at coding position 2002 of the PCCA gene that results in a glycine to arginine amino acid change at residue 668 of the PCCA protein. The Gly668 residue falls in the biotin carboxyl carrier protein domain which is critical to PCCA's role in the biotinylation and catabolism of certain amino acids (PMID: 20725044). This is a previously reported variant (ClinVar) that has been observed in individuals affected by propionic acidemia (PMID: 10329019, 27227689, 29978829). This variant is present in 3 of 251,414 alleles (0.001%) in the gnomAD population database. Multiple bioinformatic tools predict that this glycine to arginine amino acid change would be damaging, and the glycine residue is strongly conserved at this position across the vertebrate species examined. Functiol studies have observed that this variant abolishes the biotinylating activity of the protein resulting from this variant (PMID: 10329019, 12385775). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM2, PP3, PS3
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 replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 668 of the PCCA protein (p.Gly668Arg). This variant is present in population databases (rs771438170, gnomAD 0.01%). This missense change has been observed in individuals with propionic acidemia (PMID: 10329019, 19099776, 27227689, 29978829). ClinVar contains an entry for this variant (Variation ID: 218266). 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 PCCA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PCCA function (PMID: 10329019, 12385775). For these reasons, this variant has been classified as Pathogenic.
Comment:
PCCA: PM3:Very Strong, PM2, PS3:Supporting
Comment:
This sequence variant is a single nucleotide substitution (G>A) at coding position 2002 of the PCCA gene that results in a glycine to arginine amino acid change at residue 668 of the PCCA protein. The Gly668 residue falls in the biotin carboxyl carrier protein domain which is critical to PCCA's role in the biotinylation and catabolism of certain amino acids (PMID: 20725044). This is a previously reported variant (ClinVar) that has been observed in individuals affected by propionic acidemia (PMID: 10329019, 27227689, 29978829). This variant is present in 3 of 251,414 alleles (0.001%) in the gnomAD population database. Multiple bioinformatic tools predict that this glycine to arginine amino acid change would be damaging, and the glycine residue is strongly conserved at this position across the vertebrate species examined. Functiol studies have observed that this variant abolishes the biotinylating activity of the protein resulting from this variant (PMID: 10329019, 12385775). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM2, PP3, PS3
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Novel Heterozygous PCCA Mutations with Fatal Outcome in Propionic Acidemia. | Yang B | Indian pediatrics | 2018 | PMID: 29978829 |
| 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 |
| Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase. | Huang CS | Nature | 2010 | PMID: 20725044 |
| [Gene mutation analysis in patients with propionic acidemia]. | Hu YH | Zhonghua er ke za zhi = Chinese journal of pediatrics | 2008 | PMID: 19099776 |
| Functional characterization of PCCA mutations causing propionic acidemia. | Clavero S | Biochimica et biophysica acta | 2002 | PMID: 12385775 |
| Coding sequence mutations in the alpha subunit of propionyl-CoA carboxylase in patients with propionic acidemia. | Campeau E | Molecular genetics and metabolism | 1999 | PMID: 10329019 |
Text-mined citations for rs771438170 ...
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 Nov 19, 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.