ClinVar Genomic variation as it relates to human health
NM_000282.4(PCCA):c.1284+1G>A
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.1284+1G>A
Variation ID: 279863 Accession: VCV000279863.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q32.3 13: 100302999 (GRCh38) [ NCBI UCSC ] 13: 100955253 (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 Dec 6, 2016 Feb 28, 2024 Jan 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000282.4:c.1284+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001127692.3:c.1206+1G>A splice donor NM_001178004.2:c.1284+1G>A splice donor NM_001352605.2:c.1284+1G>A splice donor NM_001352606.2:c.1140+1G>A splice donor NM_001352607.2:c.1206+1G>A splice donor NM_001352608.2:c.1062+1G>A splice donor NM_001352609.2:c.1284+1G>A splice donor NM_001352610.2:c.339+1G>A splice donor NM_001352611.2:c.339+1G>A splice donor NM_001352612.2:c.195+1G>A splice donor NC_000013.11:g.100302999G>A NC_000013.10:g.100955253G>A NG_008768.1:g.218917G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000013.11:100302998:G:A
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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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00007
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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PCCA | - | - |
GRCh38 GRCh37 |
1335 | 1455 |
Conditions - Germline
Condition
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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 (1) |
criteria provided, single submitter
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Jul 19, 2018 | RCV000382350.1 | |
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 7, 2024 | RCV000670117.17 | |
PCCA-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2022 | RCV003409392.4 |
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
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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
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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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Pathogenic
(Jul 19, 2018)
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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: SCV000329454.5
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The c.1284+1G>A pathogenic variant in the PCCA gene has been reported previously in the homozygous state in an individual with propionic acidemia (Vatanavicharn et al., … (more)
The c.1284+1G>A pathogenic variant in the PCCA gene has been reported previously in the homozygous state in an individual with propionic acidemia (Vatanavicharn et al., 2014). This splice site variant destroys the canonical splice donor site in intron 14. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1284+1G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1284+1G>A as a pathogenic variant. (less)
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Likely pathogenic
(Oct 25, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000914607.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The PCCA c.1284+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.1284+1G>A … (more)
The PCCA c.1284+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.1284+1G>A variant has been reported in four studies in which it is found in four individuals with propionic academia, including in one in a homozygous state, in two in a compound heterozygous state, and in one in a heterozygous state (Campeau et al. 2001; Vatanavicharn et al. 2014; Cappuccio et al. 2016; Longo et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Genome Aggregation Database. RT-PCR analysis indicated that the c.1284+1G>A variant results in the skipping of exons 13 and 14 (Campeau et al. 2001). Based on the evidence and the potential impact of splice donor variants, the c.1284+1G>A variant is classified as likely pathogenic for propionic academia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 07, 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: SCV001362340.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 05, 2021 |
Comment:
Variant summary: PCCA c.1284+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: PCCA c.1284+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication confirmed this prediction by reporting RT-PCR analysis of patient derived mRNA that revealed skipping of exons 13 and 14 (V356_G428del73) (Campeau_2001). The variant allele was found at a frequency of 3.6e-05 in 251288 control chromosomes. c.1284+1G>A has been reported in the literature in individuals affected with Propionic Acidemia (example, Campeau_2001, Vatanavicharn_2014, Cappuccio_2016, Longo_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal propionyl-CoA carboxylase activity in a patient with a compound heterozygous genotype (Longo_2017). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Apr 16, 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: SCV002813969.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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PCCA-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004112918.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PCCA c.1284+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous … (more)
The PCCA c.1284+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous or presumed compound heterozygous state in several patients with propionic acidemia (Vatanavicharn et al. 2014. PubMed ID: 24464666; Cappuccio et al. 2017. PubMed ID: 27900673; Longo et al. 2017. PubMed ID: 28712602). Based on RT-PCR analysis, this variant was reported to lead to skipping of exons 13 and 14 (Campeau et al. 2001. PubMed ID: 11592820, reported as IVS14+1G>A), which affects the biotin carboxylase domain (Vatanavicharn et al. 2014. PubMed ID: 24464666). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-100955253-G-A). Based on the collective evidence, we classify this variant as pathogenic. (less)
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Pathogenic
(Aug 07, 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: SCV004202861.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 07, 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: SCV001201116.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects a donor splice site in intron 14 of the PCCA gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 14 of the PCCA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PCCA are known to be pathogenic (PMID: 15464417). This variant is present in population databases (rs752761437, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with propionic acidemia (PMID: 24464666, 27900673, 28712602). ClinVar contains an entry for this variant (Variation ID: 279863). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 19, 2017)
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no assertion criteria provided
Method: clinical testing
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Propionic acidemia
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000794933.2
First in ClinVar: Aug 05, 2018 Last updated: Dec 23, 2019 |
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Pathogenic
(Aug 25, 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: SCV002094975.1
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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Propionyl-CoA carboxylase - A review. | Wongkittichote P | Molecular genetics and metabolism | 2017 | PMID: 29033250 |
Anaplerotic therapy in propionic acidemia. | Longo N | Molecular genetics and metabolism | 2017 | PMID: 28712602 |
Expansion of the Phenotypic Spectrum of Propionic Acidemia with Isolated Elevated Propionylcarnitine. | Cappuccio G | JIMD reports | 2017 | PMID: 27900673 |
Clinical characteristics and mutation analysis of propionic acidemia in Thailand. | Vatanavicharn N | World journal of pediatrics : WJP | 2014 | PMID: 24464666 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Propionic acidemia: mutation update and functional and structural effects of the variant alleles. | Desviat LR | Molecular genetics and metabolism | 2004 | PMID: 15464417 |
Structure of the PCCA gene and distribution of mutations causing propionic acidemia. | Campeau E | Molecular genetics and metabolism | 2001 | PMID: 11592820 |
Text-mined citations for rs752761437 ...
HelpRecord last updated May 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.