ClinVar Genomic variation as it relates to human health
NM_000282.4(PCCA):c.923dup (p.Leu308fs)
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.923dup (p.Leu308fs)
Variation ID: 310846 Accession: VCV000310846.23
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 13q32.3 13: 100273197-100273198 (GRCh38) [ NCBI UCSC ] 13: 100925451-100925452 (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 Mar 16, 2024 Dec 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000282.4:c.923dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000273.2:p.Leu308fs frameshift NM_000282.3:c.917dupT NM_000282.3:c.923dup NM_001127692.3:c.845dup NP_001121164.1:p.Leu282fs frameshift NM_001178004.2:c.923dup NP_001171475.1:p.Leu308fs frameshift NM_001352605.2:c.923dup NP_001339534.1:p.Leu308fs frameshift NM_001352606.2:c.923dup NP_001339535.1:p.Leu308fs frameshift NM_001352607.2:c.845dup NP_001339536.1:p.Leu282fs frameshift NM_001352608.2:c.845dup NP_001339537.1:p.Leu282fs frameshift NM_001352609.2:c.923dup NP_001339538.1:p.Leu308fs frameshift NM_001352610.2:c.-23dup 5 prime UTR NM_001352611.2:c.-23dup 5 prime UTR NM_001352612.2:c.-23dup 5 prime UTR NR_148027.2:n.951dup non-coding transcript variant NR_148028.2:n.951dup non-coding transcript variant NR_148029.2:n.873dup non-coding transcript variant NR_148030.2:n.951dup non-coding transcript variant NR_148031.2:n.951dup non-coding transcript variant NC_000013.11:g.100273204dup NC_000013.10:g.100925458dup NG_008768.1:g.189122dup - Protein change
- L308fs, L282fs
- Other names
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- Canonical SPDI
- NC_000013.11:100273197:TTTTTTT:TTTTTTTT
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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.
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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 (8) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2023 | RCV000335150.16 | |
Pathogenic (2) |
no assertion criteria provided
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- | RCV001528768.3 | |
PCCA-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Dec 31, 2023 | RCV003977915.1 |
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
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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
(Apr 05, 2019)
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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: SCV000382013.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The PCCA c.923dupT (p.Leu308PhefsTer35) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Leu308PhefsTer35 variant has been … (more)
The PCCA c.923dupT (p.Leu308PhefsTer35) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Leu308PhefsTer35 variant has been reported in at least four studies in which it was identified in a total of 10 individuals affected with propionic acidemia, including in three in a homozygous state and in seven in a compound heterozygous state (Yang et al. 2004; Gallego-Villar et al. 2013; Witters et al. 2016; Molema et al. 2018). Control data are unavailable for the variant which is reported at a frequency of 0.000062 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Leu308PhefsTer35 variant is classified as pathogenic for propionic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jun 25, 2019)
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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: SCV001362337.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PCCA c.923dupT (p.Leu308PhefsX35) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: PCCA c.923dupT (p.Leu308PhefsX35) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory (c.937C>T, p.Arg313X). The variant allele was found at a frequency of 3.2e-05 in 250614 control chromosomes. The variant, c.923dupT, has been reported in the literature in multiple individuals affected with Propionic Acidemia (Perez_2003, Yang_2004). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 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: SCV002801629.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 31, 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: SCV001228999.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu308Phefs*35) in the PCCA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Leu308Phefs*35) in the PCCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCCA are known to be pathogenic (PMID: 15464417). This variant is present in population databases (rs573607437, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with propionic acidemia (PMID: 12559849, 20549364, 22033733, 27900673). This variant is also known as 917-923insT F307fs. ClinVar contains an entry for this variant (Variation ID: 310846). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 30, 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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Baylor Genetics
Accession: SCV004202907.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 31, 2023)
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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: SCV004788536.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The PCCA c.923dupT variant is predicted to result in a frameshift and premature protein termination (p.Leu308Phefs*35). This variant was reported in multiple individuals with Propionic … (more)
The PCCA c.923dupT variant is predicted to result in a frameshift and premature protein termination (p.Leu308Phefs*35). This variant was reported in multiple individuals with Propionic acidaemia (see example: reported as 917–923insT in Table 2, Perez et al 2003. PubMed ID: 12559849; Cappuccio G et al 2016. PubMed ID: 27900673). This variant is reported in 0.0097% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Frameshift variants in PCCA are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(May 08, 2019)
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no assertion criteria provided
Method: clinical testing
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Propionic acidemia
Affected status: yes
Allele origin:
inherited
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Laboratory of Metabolic Disorders, Peking University First Hospital
Accession: SCV000929818.1
First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019 |
Ethnicity/Population group: Chinese
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Pathogenic
(Nov 13, 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: SCV001132451.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741085.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973410.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Oct 21, 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: SCV002094971.1
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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Fibroblast growth factor 21 as a biomarker for long-term complications in organic acidemias. | Molema F | Journal of inherited metabolic disease | 2018 | PMID: 30159853 |
Expansion of the Phenotypic Spectrum of Propionic Acidemia with Isolated Elevated Propionylcarnitine. | Cappuccio G | JIMD reports | 2017 | PMID: 27900673 |
Autism in patients with propionic acidemia. | Witters P | Molecular genetics and metabolism | 2016 | PMID: 27825584 |
Functional characterization of novel genotypes and cellular oxidative stress studies in propionic acidemia. | Gallego-Villar L | Journal of inherited metabolic disease | 2013 | PMID: 23053474 |
Mutation analysis in 54 propionic acidemia patients. | Kraus JP | Journal of inherited metabolic disease | 2012 | PMID: 22033733 |
The molecular landscape of propionic acidemia and methylmalonic aciduria in Latin America. | Pérez B | Journal of inherited metabolic disease | 2010 | PMID: 20549364 |
Propionic acidemia: mutation update and functional and structural effects of the variant alleles. | Desviat LR | Molecular genetics and metabolism | 2004 | PMID: 15464417 |
Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia. | Yang X | Molecular genetics and metabolism | 2004 | PMID: 15059621 |
Propionic acidemia: identification of twenty-four novel mutations in Europe and North America. | Pérez B | Molecular genetics and metabolism | 2003 | PMID: 12559849 |
Text-mined citations for rs573607437 ...
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.