ClinVar Genomic variation as it relates to human health
NM_000532.5(PCCB):c.1283C>T (p.Thr428Ile)
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.1283C>T (p.Thr428Ile)
Variation ID: 12016 Accession: VCV000012016.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q22.3 3: 136327239 (GRCh38) [ NCBI UCSC ] 3: 136046081 (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 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000532.5:c.1283C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000523.2:p.Thr428Ile missense NM_001178014.2:c.1343C>T NP_001171485.1:p.Thr448Ile missense NC_000003.12:g.136327239C>T NC_000003.11:g.136046081C>T NG_008939.1:g.81915C>T P05166:p.Thr428Ile - Protein change
- T428I, T448I
- Other names
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- Canonical SPDI
- NC_000003.12:136327238: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.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 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
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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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PCCB | - | - |
GRCh38 GRCh37 |
1148 | 1173 |
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. |
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Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV000012796.33 |
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
(Apr 02, 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: SCV000798999.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Pathogenic
(Nov 26, 2021)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049495.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The PCCB c.1283C>T, p.Thr428Ile variant (rs111033542) is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with propionic acidemia … (more)
The PCCB c.1283C>T, p.Thr428Ile variant (rs111033542) is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with propionic acidemia (Kim 2003, Yang 2004, Yorifugi 2002). This variant is also reported in ClinVar (Variation ID: 12016) and is found in the general population with an allele frequency of 0.002% (6/251014 alleles) in the Genome Aggregation Database. The threonine at codon 428 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.922). Based on available information, this variant is considered to be pathogenic. References: Kim SN et al. Molecular analysis of PCCB gene in Korean patients with propionic acidemia. Mol Genet Metab. 2002 Nov;77(3):209-16. PMID: 12409268. Yang X et al. Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia. Mol Genet Metab. 2004 Apr;81(4):335-42. PMID: 15059621. Yorifuji T et al. Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications. Hum Genet. 2002 Aug;111(2):161-5. PMID: 12189489. (less)
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Pathogenic
(Oct 06, 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: SCV004205192.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jul 08, 2016)
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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: SCV000697268.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
Variant summary: The c.1283C>T (p.Tre428Ile) in PCCB gene is a missense change that alters a highly conserved nucleotide and 5/5 in silico tools predict deleterious … (more)
Variant summary: The c.1283C>T (p.Tre428Ile) in PCCB gene is a missense change that alters a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant falls into the carboxyl-terminal portion of the b-subunit and mutations in this region are likely to diminish the ability of the mutant bPCC proteins to form PCC active oligomers. These predictions were also confirmed by functional studies, where no detectable enzymatic activities were found in fibroblasts of a patient homozygous T428I. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00002 (3/121052 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in PCCB gene (0.0025). The variant was found in multiple affected individuals with established dx of propionic acidemia. Kim (2002) and Ohura (1993) report the frequency of the variant of interest in affected individuals as 56.3% and 50%, respectively. Lastly, a reputable database/diagnostic center classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic. (less)
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Pathogenic
(Feb 15, 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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Revvity Omics, Revvity
Accession: SCV002016543.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 19, 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: SCV002189281.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 428 of the PCCB protein (p.Thr428Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 428 of the PCCB protein (p.Thr428Ile). This variant is present in population databases (rs111033542, gnomAD 0.02%). This missense change has been observed in individual(s) with propionic acidemia (PMID: 8295402, 12409268). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12016). 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: 8852656). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 1993)
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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: SCV000033036.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In Japanese patients with propionic acidemia (606054), Ohura et al. (1993) identified a 1283C-T change in the PCCB gene, resulting in a thr428-to-ile substitution.
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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: SCV001454527.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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: SCV000055679.2
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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Propionic Acidemia. | Adam MP | - | 2016 | PMID: 22593918 |
Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia. | Yang X | Molecular genetics and metabolism | 2004 | PMID: 15059621 |
Molecular analysis of PCCB gene in Korean patients with propionic acidemia. | Kim SN | Molecular genetics and metabolism | 2002 | PMID: 12409268 |
Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications. | Yorifuji T | Human genetics | 2002 | PMID: 12189489 |
Chaperonin-mediated assembly of wild-type and mutant subunits of human propionyl-CoA carboxylase expressed in Escherichia coli. | Kelson TL | Human molecular genetics | 1996 | PMID: 8852656 |
Propionic acidaemia: sequence analysis of mutant mRNAs from Japanese beta subunit-deficient patients. | Ohura T | Journal of inherited metabolic disease | 1993 | PMID: 8295402 |
Text-mined citations for rs111033542 ...
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.