ClinVar Genomic variation as it relates to human health
NM_000532.5(PCCB):c.1316A>G (p.Tyr439Cys)
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.1316A>G (p.Tyr439Cys)
Variation ID: 225429 Accession: VCV000225429.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q22.3 3: 136327650 (GRCh38) [ NCBI UCSC ] 3: 136046492 (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 May 25, 2017 Feb 14, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000532.5:c.1316A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000523.2:p.Tyr439Cys missense NM_001178014.2:c.1376A>G NP_001171485.1:p.Tyr459Cys missense NC_000003.12:g.136327650A>G NC_000003.11:g.136046492A>G NG_008939.1:g.82326A>G - Protein change
- Y439C, Y459C
- Other names
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- Canonical SPDI
- NC_000003.12:136327649:A:G
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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
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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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000490483.7 |
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
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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
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Propionic acidemia
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267437.1
First in ClinVar: May 25, 2017 Last updated: May 25, 2017 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Likely pathogenic
(Jul 20, 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: SCV000792715.1
First in ClinVar: May 25, 2017 Last updated: May 25, 2017 |
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Pathogenic
(Jun 07, 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: SCV000919959.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: PCCB c.1316A>G (p.Tyr439Cys) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) of the encoded protein … (more)
Variant summary: PCCB c.1316A>G (p.Tyr439Cys) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (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 2e-05 in 246228 control chromosomes, mostly occuring in the East Asian subpopulation. c.1316A>G has been reported in the literature in individuals affected with Propionic Acidemia; all of these cases were found in East Asian populations (Kim 2002, Yorifuji 2002, Chiu 2014). These data indicate that the variant is likely to be associated with disease. These publications also reported a significantly decreased enzyme activity in the affected individuals, with the most pronounced variant effect resulting in <10% of normal activity. A recent population study demonstrated a founder effect for the variant in the Korean population based on haplotype analysis (Park 2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 08, 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: SCV004205204.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 24, 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: SCV001580904.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 439 of the PCCB protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 439 of the PCCB protein (p.Tyr439Cys). This variant is present in population databases (rs769521436, gnomAD 0.02%). This missense change has been observed in individual(s) with PCCB-related conditions (PMID: 12189489, 12409268, 31808324). ClinVar contains an entry for this variant (Variation ID: 225429). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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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 with Novel Mutation Presenting as Recurrent Pancreatitis in a Child. | Choe JY | Journal of Korean medical science | 2019 | PMID: 31808324 |
A Population-Based Genomic Study of Inherited Metabolic Diseases Detected Through Newborn Screening. | Park KJ | Annals of laboratory medicine | 2016 | PMID: 27578510 |
Two frequent mutations associated with the classic form of propionic acidemia in Taiwan. | Chiu YH | Biochemical genetics | 2014 | PMID: 24863100 |
Propionic acidemia: mutation update and functional and structural effects of the variant alleles. | Desviat LR | Molecular genetics and metabolism | 2004 | PMID: 15464417 |
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 |
Text-mined citations for rs769521436 ...
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.