This variant is a 4 bp deletion starting at position +4 of intron 21 of the PCCA gene and is predicted to affect native splicing by in-silico tools. This variant, named 1824IVS+3del4, has been previously reported as a homozygous change in an individual with propionic acidemia and moderate psychomotor delay (PMID: 10780784, 9385377). The PCC enzyme activity in the patient's fibroblasts was significantly lower than the normal control (PMID: 10780784). The c.1899+4_1899+7del is also reported in the literature as IVS21+3del4 (PMID: 15235904). Splicing studies in patient's fibroblasts demonstrated that this variant leads to skipping of exon 21 and residual low levels of normal splicing (PMID: 9385377, 15235904). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0059% (9/152424) and thus is presumed to be rare. Based on the available evidence, the c.1899+4_1899+7del variant is classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000282.4(PCCA):c.1899+4_1899+7del
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000282.4(PCCA):c.1899+4_1899+7del
Variation ID: 195560 Accession: VCV000195560.16
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 13q32.3 13: 100449306-100449309 (GRCh38) [ NCBI UCSC ] 13: 101101560-101101563 (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 Jun 28, 2015 Jun 17, 2024 Mar 30, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000282.4:c.1899+4_1899+7del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_000282.3:c.1899+4_1899+7delAGTA NM_001127692.3:c.1821+4_1821+7del splice donor NM_001178004.2:c.1899+4_1899+7del splice donor NM_001352605.2:c.1845+23578_1845+23581del intron variant NM_001352606.2:c.1755+4_1755+7del splice donor NM_001352607.2:c.1821+4_1821+7del splice donor NM_001352608.2:c.1677+4_1677+7del splice donor NM_001352609.2:c.1899+4_1899+7del splice donor NM_001352610.2:c.954+4_954+7del splice donor NM_001352611.2:c.900+23578_900+23581del intron variant NM_001352612.2:c.810+4_810+7del splice donor NC_000013.11:g.100449309_100449312del NC_000013.10:g.101101563_101101566del NG_008768.1:g.365227_365230del - Protein change
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- Other names
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- Canonical SPDI
- NC_000013.11:100449305:GTAAGTA:GTA
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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
Help
The frequency of the allele represented by this VCV record.
- -
- Links
- Comment on variant
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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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| PCCA | - | - |
GRCh38 GRCh37 |
1370 | 1491 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2014 | RCV000176154.4 | |
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2024 | RCV001066663.13 |
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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|---|---|---|---|---|---|
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Pathogenic
(Dec 02, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000227764.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 2
Sex: mixed
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Likely pathogenic
(Jun 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
PROPIONIC ACIDEMIA
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984842.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
This variant is a 4 bp deletion starting at position +4 of intron 21 of the PCCA gene and is predicted to affect native splicing … (more)
This variant is a 4 bp deletion starting at position +4 of intron 21 of the PCCA gene and is predicted to affect native splicing by in-silico tools. This variant, named 1824IVS+3del4, has been previously reported as a homozygous change in an individual with propionic acidemia and moderate psychomotor delay (PMID: 10780784, 9385377). The PCC enzyme activity in the patient's fibroblasts was significantly lower than the normal control (PMID: 10780784). The c.1899+4_1899+7del is also reported in the literature as IVS21+3del4 (PMID: 15235904). Splicing studies in patient's fibroblasts demonstrated that this variant leads to skipping of exon 21 and residual low levels of normal splicing (PMID: 9385377, 15235904). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0059% (9/152424) and thus is presumed to be rare. Based on the available evidence, the c.1899+4_1899+7del variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Jun 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001431999.2
First in ClinVar: Sep 14, 2020 Last updated: Aug 03, 2022 |
Comment:
Variant summary: PCCA c.1899+4_1899+7delAGTA alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: PCCA c.1899+4_1899+7delAGTA alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. At least one publication reports experimental evidence that this variant affects mRNA splicing. In functional studies, the variant resulted in an in-frame deletion of 18 amino acids as a result of exon skipping (Richard_1997, Clavero_2004). It was also reported that small levels of (3-16%) of correctly spliced transcript were found in a homozygous patient, which was sufficient to permit the development of a mild phenotype (Clavero_2004). The variant allele was found at a frequency of 5.9e-05 in 152424 control chromosomes (gnomAD). c.1899+4_1899+7delAGTA has been reported in the literature in multiple individuals affected with Propionic Acidemia (Richard_1997, Kraus_2012, Stanescu_2021). These data indicate that the variant is very likely to be associated with disease. Two assessments for this variant have been submitted to ClinVar after 2014. One submitter classified the variant as pathogenic and the other classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Mar 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002807372.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Jan 20, 2024)
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criteria provided, single submitter
Method: clinical testing
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Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001231679.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 21 of the PCCA gene. It does not directly change the encoded amino acid sequence of the PCCA protein. … (more)
This sequence change falls in intron 21 of the PCCA gene. It does not directly change the encoded amino acid sequence of the PCCA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs794727334, gnomAD 0.03%). This variant has been observed in individual(s) with propionic acidemia (PMID: 9385377, 10101253, 10780784, 22033733). This variant is also known as 1824IVS+3del4 and IVS21+3del4. ClinVar contains an entry for this variant (Variation ID: 195560). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 21, but is expected to preserve the integrity of the reading-frame (PMID: 9385377, 15235904). For these reasons, this variant has been classified as Pathogenic. (less)
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|
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Likely pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202841.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Aug 01, 2004)
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no assertion criteria provided
Method: literature only
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PROPIONIC ACIDEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033040.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 23, 2021 |
Comment on evidence:
Richard et al. (1997) identified a 4-bp (AAGT) deletion in the intron downstream from nucleotide 1824 in the PCCA gene in an 18-year-old patient with … (more)
Richard et al. (1997) identified a 4-bp (AAGT) deletion in the intron downstream from nucleotide 1824 in the PCCA gene in an 18-year-old patient with a late-onset, relatively mild form of propionic acidemia (606054) reported by Merinero et al. (1981). The diagnosis was made at the age of 17 months. The patient demonstrated a favorable response to restriction of dietary protein, and psychomotor development was adequate. The mutation was present in homozygous form. Clavero et al. (2004) performed mRNA analysis of a fibroblast cell line from the patient reported by Richard et al. (1997) to test for the presence of normally spliced transcripts which might explain the patient's mild phenotype. Very low levels of normal-sized transcript were detectable by ethidium bromide staining; quantitative RT-PCR revealed 30-fold less correctly spliced PCCA mRNA in the patient's fibroblasts than in normal control fibroblasts. Clavero et al. (2004) suggested that very low levels of correctly spliced transcript are sufficient to permit development of the mild phenotype. (less)
|
Comment:
Comment:
Variant summary: PCCA c.1899+4_1899+7delAGTA alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. At least one publication reports experimental evidence that this variant affects mRNA splicing. In functional studies, the variant resulted in an in-frame deletion of 18 amino acids as a result of exon skipping (Richard_1997, Clavero_2004). It was also reported that small levels of (3-16%) of correctly spliced transcript were found in a homozygous patient, which was sufficient to permit the development of a mild phenotype (Clavero_2004). The variant allele was found at a frequency of 5.9e-05 in 152424 control chromosomes (gnomAD). c.1899+4_1899+7delAGTA has been reported in the literature in multiple individuals affected with Propionic Acidemia (Richard_1997, Kraus_2012, Stanescu_2021). These data indicate that the variant is very likely to be associated with disease. Two assessments for this variant have been submitted to ClinVar after 2014. One submitter classified the variant as pathogenic and the other classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change falls in intron 21 of the PCCA gene. It does not directly change the encoded amino acid sequence of the PCCA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs794727334, gnomAD 0.03%). This variant has been observed in individual(s) with propionic acidemia (PMID: 9385377, 10101253, 10780784, 22033733). This variant is also known as 1824IVS+3del4 and IVS21+3del4. ClinVar contains an entry for this variant (Variation ID: 195560). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 21, but is expected to preserve the integrity of the reading-frame (PMID: 9385377, 15235904). For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
This variant is a 4 bp deletion starting at position +4 of intron 21 of the PCCA gene and is predicted to affect native splicing by in-silico tools. This variant, named 1824IVS+3del4, has been previously reported as a homozygous change in an individual with propionic acidemia and moderate psychomotor delay (PMID: 10780784, 9385377). The PCC enzyme activity in the patient's fibroblasts was significantly lower than the normal control (PMID: 10780784). The c.1899+4_1899+7del is also reported in the literature as IVS21+3del4 (PMID: 15235904). Splicing studies in patient's fibroblasts demonstrated that this variant leads to skipping of exon 21 and residual low levels of normal splicing (PMID: 9385377, 15235904). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0059% (9/152424) and thus is presumed to be rare. Based on the available evidence, the c.1899+4_1899+7del variant is classified as Likely Pathogenic.
Comment:
Variant summary: PCCA c.1899+4_1899+7delAGTA alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. At least one publication reports experimental evidence that this variant affects mRNA splicing. In functional studies, the variant resulted in an in-frame deletion of 18 amino acids as a result of exon skipping (Richard_1997, Clavero_2004). It was also reported that small levels of (3-16%) of correctly spliced transcript were found in a homozygous patient, which was sufficient to permit the development of a mild phenotype (Clavero_2004). The variant allele was found at a frequency of 5.9e-05 in 152424 control chromosomes (gnomAD). c.1899+4_1899+7delAGTA has been reported in the literature in multiple individuals affected with Propionic Acidemia (Richard_1997, Kraus_2012, Stanescu_2021). These data indicate that the variant is very likely to be associated with disease. Two assessments for this variant have been submitted to ClinVar after 2014. One submitter classified the variant as pathogenic and the other classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change falls in intron 21 of the PCCA gene. It does not directly change the encoded amino acid sequence of the PCCA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs794727334, gnomAD 0.03%). This variant has been observed in individual(s) with propionic acidemia (PMID: 9385377, 10101253, 10780784, 22033733). This variant is also known as 1824IVS+3del4 and IVS21+3del4. ClinVar contains an entry for this variant (Variation ID: 195560). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 21, but is expected to preserve the integrity of the reading-frame (PMID: 9385377, 15235904). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Long-term follow-up with filter paper samples in patients with propionic acidemia. | Stanescu S | JIMD reports | 2020 | PMID: 33473339 |
| Prediction of mutant mRNA splice isoforms by information theory-based exon definition. | Mucaki EJ | Human mutation | 2013 | PMID: 23348723 |
| Mutation analysis in 54 propionic acidemia patients. | Kraus JP | Journal of inherited metabolic disease | 2012 | PMID: 22033733 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Qualitative and quantitative analysis of the effect of splicing mutations in propionic acidemia underlying non-severe phenotypes. | Clavero S | Human genetics | 2004 | PMID: 15235904 |
| Functional characterization of PCCA mutations causing propionic acidemia. | Clavero S | Biochimica et biophysica acta | 2002 | PMID: 12385775 |
| Potential relationship between genotype and clinical outcome in propionic acidaemia patients. | Pérez-Cerdá C | European journal of human genetics : EJHG | 2000 | PMID: 10780784 |
| Genetic heterogeneity in propionic acidemia patients with alpha-subunit defects. Identification of five novel mutations, one of them causing instability of the protein. | Richard E | Biochimica et biophysica acta | 1999 | PMID: 10101253 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Three novel splice mutations in the PCCA gene causing identical exon skipping in propionic acidemia patients. | Richard E | Human genetics | 1997 | PMID: 9385377 |
| Late onset type of propionic acidaemia: case report and biochemical studies. | Merinero B | Journal of inherited metabolic disease | 1981 | PMID: 6790853 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PCCA | - | - | - | - |
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Text-mined citations for rs794727334 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.
NCBI staff provided an HGVS expression for allelic variant 232000.0001 based on the sequence reported in Figure 2 of the paper by Richard et al., 1997 (PubMed 9385377).