ClinVar Genomic variation as it relates to human health
NM_000532.5(PCCB):c.1228C>T (p.Arg410Trp)
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.1228C>T (p.Arg410Trp)
Variation ID: 12011 Accession: VCV000012011.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q22.3 3: 136327184 (GRCh38) [ NCBI UCSC ] 3: 136046026 (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 Aug 4, 2024 Feb 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000532.5:c.1228C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000523.2:p.Arg410Trp missense NM_001178014.2:c.1288C>T NP_001171485.1:p.Arg430Trp missense NC_000003.12:g.136327184C>T NC_000003.11:g.136046026C>T NG_008939.1:g.81860C>T P05166:p.Arg410Trp - Protein change
- R410W, R430W
- Other names
- R412W
- Canonical SPDI
- NC_000003.12:136327183: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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00006
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
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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 |
1164 | 1189 |
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
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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 (9) |
criteria provided, multiple submitters, no conflicts
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Feb 25, 2024 | RCV000012791.35 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2023 | RCV004589508.1 |
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
(Jan 17, 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: SCV000789286.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Pathogenic
(May 28, 2019)
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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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Mendelics
Accession: SCV001136613.1
First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020 |
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Pathogenic
(Mar 13, 2020)
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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: SCV001339066.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PCCB c.1228C>T (p.Arg410Trp) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal (IPR011763) of the encoded protein sequence. … (more)
Variant summary: PCCB c.1228C>T (p.Arg410Trp) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal (IPR011763) 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 2.8e-05 in 251032 control chromosomes (gnomAD). c.1228C>T has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with Propionic Acidemia (e.g. Chloupkova_2002, McCrory_2017, Kraus_2012, Gravel_1994). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was found to have reduced enzymatic activity (Kraus_2012, Perez-Cedra_2003). Three ClinVar submitters (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
(Feb 25, 2024)
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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: SCV004205186.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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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: SCV000631912.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 410 of the PCCB protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 410 of the PCCB protein (p.Arg410Trp). This variant is present in population databases (rs121964959, gnomAD 0.006%). This missense change has been observed in individuals with propionic acidemia (PMID: 8411997, 12007220, 22033733). ClinVar contains an entry for this variant (Variation ID: 12011). 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 PCCB protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PCCB function (PMID: 12757933, 15890657, 15949719). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 15, 2023)
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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: SCV005081109.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Published functional studies demonstrate a damaging effect:11.5% of wild-type propionyl-CoA carboxylase activity (PMID: 12757933); In silico analysis supports that this missense variant has a deleterious … (more)
Published functional studies demonstrate a damaging effect:11.5% of wild-type propionyl-CoA carboxylase activity (PMID: 12757933); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15059621, 8023851, 15890657, 12007220, 8411997, 12559849, 25865301, 9683601, 22033733, 15235904, 31589614, 33028371, 33473339, 35331292, 12757933) (less)
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Likely pathogenic
(Jul 25, 2023)
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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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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV005088587.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
Comment:
Biallelic loss-of-function variants in SLC13A5 are known to cause developmental and epileptic encephalopathy 25, with amelogenesis imperfecta (MIM# 615905). The clinical features observed in the … (more)
Biallelic loss-of-function variants in SLC13A5 are known to cause developmental and epileptic encephalopathy 25, with amelogenesis imperfecta (MIM# 615905). The clinical features observed in the proband, and his sibling are in concordance with developmental and epileptic encephalopathy 25, with amelogenesis imperfecta. (less)
Sex: male
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Pathogenic
(Jan 01, 1999)
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no assertion criteria provided
Method: literature only
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PROPIONIC ACIDEMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033031.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
Tahara et al. (1993) identified a C-to-T transition at nucleotide 1240, which replaced arg412 with tryptophan in the predicted amino acid sequence. This change was … (more)
Tahara et al. (1993) identified a C-to-T transition at nucleotide 1240, which replaced arg412 with tryptophan in the predicted amino acid sequence. This change was found in 3 patients with propionic acidemia (606054), all Japanese, of whom 2 were sibs; all were homozygous for the transition. The mutation was in the same exon as the insertion/deletion described by Tahara et al. (1990) and was detected only in Caucasian patients, among whom it represented 11 of 34 mutant alleles. (This mutation was described as a C-to-T transition at nucleotide 1228 in exon 12, causing an ARG410TRP substitution, by Ugarte et al. (1999).) (less)
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Pathogenic
(Jan 15, 2021)
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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: SCV002081489.1
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: SCV000055678.2
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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Comparison of Methods of Initial Ascertainment in 58 Cases of Propionic Acidemia Enrolled in the Inborn Errors of Metabolism Information System Reveals Significant Differences in Time to Evaluation and Symptoms at Presentation. | McCrory NM | The Journal of pediatrics | 2017 | PMID: 27776753 |
Propionic Acidemia. | Adam MP | - | 2016 | PMID: 22593918 |
Mutation analysis in 54 propionic acidemia patients. | Kraus JP | Journal of inherited metabolic disease | 2012 | PMID: 22033733 |
Towards a model to explain the intragenic complementation in the heteromultimeric protein propionyl-CoA carboxylase. | Rodríguez-Pombo P | Biochimica et biophysica acta | 2005 | PMID: 15949719 |
Characterization of four variant forms of human propionyl-CoA carboxylase expressed in Escherichia coli. | Jiang H | The Journal of biological chemistry | 2005 | PMID: 15890657 |
Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia. | Yang X | Molecular genetics and metabolism | 2004 | PMID: 15059621 |
Functional analysis of PCCB mutations causing propionic acidemia based on expression studies in deficient human skin fibroblasts. | Pérez-Cerdá C | Biochimica et biophysica acta | 2003 | PMID: 12757933 |
Propionic acidemia: analysis of mutant propionyl-CoA carboxylase enzymes expressed in Escherichia coli. | Chloupkova M | Human mutation | 2002 | PMID: 12007220 |
Overview of mutations in the PCCA and PCCB genes causing propionic acidemia. | Ugarte M | Human mutation | 1999 | PMID: 10502773 |
Mutations participating in interallelic complementation in propionic acidemia. | Gravel RA | American journal of human genetics | 1994 | PMID: 8023851 |
Three independent mutations in the same exon of the PCCB gene: differences between Caucasian and Japanese propionic acidaemia. | Tahara T | Journal of inherited metabolic disease | 1993 | PMID: 8411997 |
An unusual insertion/deletion in the gene encoding the beta-subunit of propionyl-CoA carboxylase is a frequent mutation in Caucasian propionic acidemia. | Tahara T | Proceedings of the National Academy of Sciences of the United States of America | 1990 | PMID: 2154743 |
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Text-mined citations for rs121964959 ...
HelpRecord last updated Aug 04, 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.