VCV000218256.12 - ClinVar

NM_000282.4(PCCA):c.2040G>A (p.Ala680=)

Germline

Classification

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)

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.

Conflicting classifications of pathogenicity
Pathogenic(6); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000282.4(PCCA):c.2040G>A (p.Ala680=)

Variation ID: 218256 Accession: VCV000218256.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q32.3 13: 100515567 (GRCh38) [ NCBI UCSC ] 13: 101167821 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jul 24, 2016	Jun 17, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000282.4:c.2040G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000273.2:p.Ala680=	synonymous
NM_001127692.3:c.1962G>A	NP_001121164.1:p.Ala654=	synonymous
NM_001178004.2:c.1900-12108G>A		intron variant
NM_001352605.2:c.1986G>A	NP_001339534.1:p.Ala662=	synonymous
NM_001352606.2:c.1896G>A	NP_001339535.1:p.Ala632=	synonymous
NM_001352607.2:c.1822-12108G>A		intron variant
NM_001352608.2:c.1818G>A	NP_001339537.1:p.Ala606=	synonymous
NM_001352610.2:c.1095G>A	NP_001339539.1:p.Ala365=	synonymous
NM_001352611.2:c.1041G>A	NP_001339540.1:p.Ala347=	synonymous
NM_001352612.2:c.951G>A	NP_001339541.1:p.Ala317=	synonymous
NR_148028.2:n.2049G>A		non-coding transcript variant
NR_148029.2:n.1971G>A		non-coding transcript variant
NR_148030.2:n.2152G>A		non-coding transcript variant
NR_148031.2:n.1965G>A		non-coding transcript variant
NC_000013.11:g.100515567G>A
NC_000013.10:g.101167821G>A
NG_008768.1:g.431485G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000013.11:100515566:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00000

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00003

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA7033876 dbSNP: rs369982920 VarSome

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
Gene	OMIM	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.
PCCA		-	-	GRCh38 GRCh37	1371	1492

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.
Propionic acidemia	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Feb 5, 2024	RCV000236921.16

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.
Pathogenic (Jan 01, 2012)	criteria provided, single submitter (Gupta et al. (Genet Test Mol Biomarkers 2016)) Method: research	Propionic Acidemia Affected status: yes Allele origin: germline	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital Study: ORGANIC ACIDURIAS Accession: SCV000256847.1 First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016 Comment: Synonymous change	Publications: PubMed (1) PubMed: 27227689 Number of individuals with the variant: 1 Age: 0-9 years
Uncertain significance (Mar 27, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Propionic acidemia Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000800685.1 First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016	Publications: PubMed (1) PubMed: 27227689
Pathogenic (Feb 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research, in vitro	Propionic acidemia Affected status: not applicable, yes Allele origin: germline, not applicable	Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics Accession: SCV001482008.1 First in ClinVar: Feb 27, 2021 Last updated: Feb 27, 2021	Comment: PS3, PM2, PM3_supportive, PP3, PP4 Observation 1: Observation 2: Method: minigene splicing assay Result: exon skipping, corresponding to r.1900_2040del (p.Tyr634_Ala680del)
Pathogenic (Mar 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Propionic acidemia (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Centre for Inherited Metabolic Diseases, Karolinska University Hospital Accession: SCV001519662.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Family history: no
Pathogenic (Jun 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Propionic acidemia Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV003836699.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Dec 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Propionic acidemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002233883.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 27227689‚ 17576681‚ 9536098‚ 33923806‚ 10329019‚ 12385775‚ 19099776‚ 29978829 Comment: This sequence change affects codon 680 of the PCCA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more) This sequence change affects codon 680 of the PCCA mRNA. It is a 'silent' change, meaning that it does not 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 (rs369982920, gnomAD 0.01%). This variant has been observed in individual(s) with propionic acidemia (PMID: 27227689). ClinVar contains an entry for this variant (Variation ID: 218256). 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 22, but is expected to preserve the integrity of the reading-frame (PMID: 33923806). This variant disrupts a region of the PCCA protein in which other variant(s) (p.Gly668Arg) have been determined to be pathogenic (PMID: 10329019, 12385775, 19099776, 27227689, 29978829). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Propionic acidemia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202831.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

This sequence change affects codon 680 of the PCCA mRNA. It is a 'silent' change, meaning that it does not 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 (rs369982920, gnomAD 0.01%). This variant has been observed in individual(s) with propionic acidemia (PMID: 27227689). ClinVar contains an entry for this variant (Variation ID: 218256). 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 22, but is expected to preserve the integrity of the reading-frame (PMID: 33923806). This variant disrupts a region of the PCCA protein in which other variant(s) (p.Gly668Arg) have been determined to be pathogenic (PMID: 10329019, 12385775, 19099776, 27227689, 29978829). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing.	Bychkov I	International journal of molecular sciences	2021	PMID: 33923806
Novel Heterozygous PCCA Mutations with Fatal Outcome in Propionic Acidemia.	Yang B	Indian pediatrics	2018	PMID: 29978829
Seventeen Novel Mutations in PCCA and PCCB Genes in Indian Propionic Acidemia Patients, and Their Outcomes.	Gupta D	Genetic testing and molecular biomarkers	2016	PMID: 27227689
[Gene mutation analysis in patients with propionic acidemia].	Hu YH	Zhonghua er ke za zhi = Chinese journal of pediatrics	2008	PMID: 19099776
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
Functional characterization of PCCA mutations causing propionic acidemia.	Clavero S	Biochimica et biophysica acta	2002	PMID: 12385775
Coding sequence mutations in the alpha subunit of propionyl-CoA carboxylase in patients with propionic acidemia.	Campeau E	Molecular genetics and metabolism	1999	PMID: 10329019
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs369982920 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000282.4(PCCA):c.2040G>A (p.Ala680=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs369982920 ...