NM_000282.4(PCCA):c.105+1G>A AND Propionic acidemia

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jul 1, 2019)

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:
RCV000235483.3

Allele description [Variation Report for NM_000282.4(PCCA):c.105+1G>A]

NM_000282.4(PCCA):c.105+1G>A

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.105+1G>A
HGVS:
  • NC_000013.11:g.100089226G>A
  • NG_008768.1:g.5144G>A
  • NM_000282.4:c.105+1G>AMANE SELECT
  • NM_001127692.2:c.105+1G>A
  • NM_001178004.1:c.105+1G>A
  • NM_001352605.2:c.105+1G>A
  • NM_001352606.2:c.105+1G>A
  • NM_001352607.2:c.105+1G>A
  • NM_001352608.2:c.105+1G>A
  • NM_001352609.2:c.105+1G>A
  • NM_001352610.2:c.-762+1G>A
  • NM_001352611.2:c.-762+1G>A
  • NM_001352612.2:c.-762+1G>A
  • NC_000013.10:g.100741480G>A
  • NM_000282.3:c.105+1G>A
Links:
dbSNP: rs879253804
NCBI 1000 Genomes Browser:
rs879253804
Molecular consequence:
  • NM_000282.4:c.105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001127692.2:c.105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001178004.1:c.105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001352605.2:c.105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001352606.2:c.105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001352607.2:c.105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001352608.2:c.105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001352609.2:c.105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001352610.2:c.-762+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001352611.2:c.-762+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001352612.2:c.-762+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000256842Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital - ORGANIC ACIDURIAScriteria provided, single submitter
Pathogenic
(Jan 1, 2013)
germlineresearch

PubMed (1)
[See all records that cite this PMID]

SCV001396576Invitaecriteria provided, single submitter
Likely pathogenic
(Jul 1, 2019)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Description

Splice site mutation

SCV000256842

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Seventeen Novel Mutations in PCCA and PCCB Genes in Indian Propionic Acidemia Patients, and Their Outcomes.

Gupta D, Bijarnia-Mahay S, Kohli S, Saxena R, Puri RD, Shigematsu Y, Yamaguchi S, Sakamoto O, Gupta N, Kabra M, Thakur S, Deb R, Verma IC.

Genet Test Mol Biomarkers. 2016 Jul;20(7):373-82. doi: 10.1089/gtmb.2016.0017. Epub 2016 May 26.

PubMed [citation]
PMID:
27227689

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933
See all PubMed Citations (4)

Details of each submission

From Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital - ORGANIC ACIDURIAS, SCV000256842.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Invitae, SCV001396576.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change affects a donor splice site in intron 1 of the PCCA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in an individual affected with propionic acidemia (PMID: 27227689). ClinVar contains an entry for this variant (Variation ID: 218251). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Jun 22, 2021

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