ClinVar Genomic variation as it relates to human health
NM_000282.4(PCCA):c.893A>G (p.Lys298Arg)
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.893A>G (p.Lys298Arg)
Variation ID: 449078 Accession: VCV000449078.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q32.3 13: 100268762 (GRCh38) [ NCBI UCSC ] 13: 100921016 (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 19, 2017 Dec 30, 2023 Jun 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000282.4:c.893A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000273.2:p.Lys298Arg missense NM_001127692.3:c.815A>G NP_001121164.1:p.Lys272Arg missense NM_001178004.2:c.893A>G NP_001171475.1:p.Lys298Arg missense NM_001352605.2:c.893A>G NP_001339534.1:p.Lys298Arg missense NM_001352606.2:c.893A>G NP_001339535.1:p.Lys298Arg missense NM_001352607.2:c.815A>G NP_001339536.1:p.Lys272Arg missense NM_001352608.2:c.815A>G NP_001339537.1:p.Lys272Arg missense NM_001352609.2:c.893A>G NP_001339538.1:p.Lys298Arg missense NM_001352610.2:c.-53A>G 5 prime UTR NM_001352611.2:c.-53A>G 5 prime UTR NM_001352612.2:c.-53A>G 5 prime UTR NR_148027.2:n.921A>G non-coding transcript variant NR_148028.2:n.921A>G non-coding transcript variant NR_148029.2:n.843A>G non-coding transcript variant NR_148030.2:n.921A>G non-coding transcript variant NR_148031.2:n.921A>G non-coding transcript variant NC_000013.11:g.100268762A>G NC_000013.10:g.100921016A>G NG_008768.1:g.184680A>G - Protein change
- K298R, K272R
- Other names
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- Canonical SPDI
- NC_000013.11:100268761: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 6, 2017 | RCV000522063.1 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 17, 2023 | RCV000664657.5 |
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
(Sep 06, 2017)
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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: SCV000616817.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The K298R variant has previously been reported in an individual with propionic acidemia who was also heterozygous for a large deletion of PCCA, although the … (more)
The K298R variant has previously been reported in an individual with propionic acidemia who was also heterozygous for a large deletion of PCCA, although the phase of these variants was not reported (Gallego-Villar et al., 2013). Functional analysis of K298R found that it is associated with 1.6% residual enzyme activity compared to wild-type (Gallego-Villar et al., 2013). The K298R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret K298R to be a likely pathogenic variant. (less)
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Pathogenic
(Feb 16, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844841.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: PCCA c.893A>G (p.Lys298Arg) results in a conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479), the ATP-grasp fold … (more)
Variant summary: PCCA c.893A>G (p.Lys298Arg) results in a conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479), the ATP-grasp fold domain (IPR011761), and the Biotin carboxylation domain (IPR011764) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251204 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.893A>G has been reported in the literature in at least one individual affected with Propionic Acidemia (e.g., Gallego-Villar_2013, Cammarata-Scalisi_2019, Shchelochkov_2019). At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant leads to a severe reduction in PCC activity (1.6% of wild-type activity) in vitro (e.g., Gallego-Villar_2013). Three ClinVar submitters (evaluation after 2014) have cited the variant, with two labs classifying the variant as likely pathogenic and one lab classifying it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 17, 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: SCV004202875.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Oct 03, 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: SCV000788657.2
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely 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: SCV001455847.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing. | Bychkov I | International journal of molecular sciences | 2021 | PMID: 33923806 |
Chronic kidney disease in propionic acidemia. | Shchelochkov OA | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31249402 |
[Clinical, biochemical and molecular findings of propionic acidemia]. | Cammarata-Scalisi F | Archivos argentinos de pediatria | 2019 | PMID: 31063319 |
Functional characterization of novel genotypes and cellular oxidative stress studies in propionic acidemia. | Gallego-Villar L | Journal of inherited metabolic disease | 2013 | PMID: 23053474 |
Text-mined citations for rs1444049793 ...
HelpRecord last updated Dec 30, 2023
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.