NM_000282.4(PCCA):c.2041-2A>G AND Propionic acidemia

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 13, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000667861.3

Allele description [Variation Report for NM_000282.4(PCCA):c.2041-2A>G]

NM_000282.4(PCCA):c.2041-2A>G

Gene:
PCCA:propionyl-CoA carboxylase subunit alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q32.3
Genomic location:
Preferred name:
NM_000282.4(PCCA):c.2041-2A>G
HGVS:
  • NC_000013.11:g.100527673A>G
  • NG_008768.1:g.443591A>G
  • NM_000282.4:c.2041-2A>GMANE SELECT
  • NM_001127692.2:c.1963-2A>G
  • NM_001178004.1:c.1900-2A>G
  • NM_001352605.2:c.1987-2A>G
  • NM_001352606.2:c.1897-2A>G
  • NM_001352607.2:c.1822-2A>G
  • NM_001352608.2:c.1819-2A>G
  • NM_001352610.2:c.1096-2A>G
  • NM_001352611.2:c.1042-2A>G
  • NM_001352612.2:c.952-2A>G
  • NC_000013.10:g.101179927A>G
  • NM_000282.3:c.2041-2A>G
Links:
dbSNP: rs776281864
NCBI 1000 Genomes Browser:
rs776281864
Molecular consequence:
  • NM_000282.4:c.2041-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001127692.2:c.1963-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001178004.1:c.1900-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001352605.2:c.1987-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001352606.2:c.1897-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001352607.2:c.1822-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001352608.2:c.1819-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001352610.2:c.1096-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001352611.2:c.1042-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001352612.2:c.952-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:
Propionic acidemia (PROP)
Synonyms:
Propionyl-CoA carboxylase deficiency; PCC deficiency; Glycinemia, ketotic; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0011628; MedGen: C0268579; Orphanet: 35; OMIM: 606054; Human Phenotype Ontology: HP:0003353

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000792372Counsylcriteria provided, single submitter
Likely pathogenic
(Jun 15, 2017)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001389676Invitaecriteria provided, single submitter
Pathogenic
(Oct 13, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Propionic acidemia: identification of twenty-four novel mutations in Europe and North America.

Pérez B, Desviat LR, Rodríguez-Pombo P, Clavero S, Navarrete R, Perez-Cerdá C, Ugarte M.

Mol Genet Metab. 2003 Jan;78(1):59-67.

PubMed [citation]
PMID:
12559849

Qualitative and quantitative analysis of the effect of splicing mutations in propionic acidemia underlying non-severe phenotypes.

Clavero S, Pérez B, Rincón A, Ugarte M, Desviat LR.

Hum Genet. 2004 Aug;115(3):239-47. Epub 2004 Jul 2.

PubMed [citation]
PMID:
15235904
See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000792372.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001389676.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change affects an acceptor splice site in intron 22 of the PCCA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs776281864, ExAC 0.02%). This variant has been observed in an individual affected with propionic acidemia (PMID: 12559849). ClinVar contains an entry for this variant (Variation ID: 552574). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 15235904). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PCCA are known to be pathogenic (PMID: 15464417). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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