NM_000532.5(PCCB):c.1540C>T (p.Arg514Ter) AND Propionic acidemia

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 13, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000235647.5

Allele description [Variation Report for NM_000532.5(PCCB):c.1540C>T (p.Arg514Ter)]

NM_000532.5(PCCB):c.1540C>T (p.Arg514Ter)

Gene:
PCCB:propionyl-CoA carboxylase subunit beta [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3q22.3
Genomic location:
Preferred name:
NM_000532.5(PCCB):c.1540C>T (p.Arg514Ter)
HGVS:
  • NC_000003.12:g.136329946C>T
  • NG_008939.1:g.84622C>T
  • NM_000532.5:c.1540C>TMANE SELECT
  • NM_001178014.1:c.1600C>T
  • NP_000523.2:p.Arg514Ter
  • NP_001171485.1:p.Arg534Ter
  • NC_000003.11:g.136048788C>T
  • NM_000532.4:c.1540C>T
Protein change:
R514*
Links:
dbSNP: rs749908889
NCBI 1000 Genomes Browser:
rs749908889
Molecular consequence:
  • NM_000532.5:c.1540C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001178014.1:c.1600C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000256889Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital - ORGANIC ACIDURIAScriteria provided, single submitter
Pathogenicgermlineresearch

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

SCV000797713Counsylcriteria provided, single submitter
Likely pathogenic
(Feb 7, 2018)
unknownclinical testing

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

Citation Link,

SCV001219898Invitaecriteria provided, single submitter
Pathogenic
(Mar 26, 2019)
germlineclinical testing

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

SCV001623158Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(May 13, 2021)
germlineclinical testing

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

Citation Link

Description

Nonsense mutation

SCV000256889

Summary from all submissions

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

Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias.

Nizon M, Ottolenghi C, Valayannopoulos V, Arnoux JB, Barbier V, Habarou F, Desguerre I, Boddaert N, Bonnefont JP, Acquaviva C, Benoist JF, Rabier D, Touati G, de Lonlay P.

Orphanet J Rare Dis. 2013 Sep 23;8:148. doi: 10.1186/1750-1172-8-148.

PubMed [citation]
PMID:
24059531
PMCID:
PMC4016503
See all PubMed Citations (6)

Details of each submission

From Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital - ORGANIC ACIDURIAS, SCV000256889.1

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

From Counsyl, SCV000797713.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001219898.2

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

Description

This sequence change results in a premature translational stop signal in the PCCB gene (p.Arg514*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acids of the PCCB protein. This variant is present in population databases (rs749908889, ExAC 0.001%). This variant has been observed in several individuals affected with proprionic acidemia (PMID: 27227689, 11136555, 24059531). ClinVar contains an entry for this variant (Variation ID: 217893). This variant has been reported to affect PCCB protein function (PMID: 11136555). For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623158.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: PCCB c.1540C>T (p.Arg514X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251236 control chromosomes. c.1540C>T has been reported in the literature in individuals affected with Propionic Acidemia (e.g. Sanchez-Alcudia_2012, Al-Jasmi_2016). These data indicate that the variant may be associated with disease. At least one publication reports that full-length protein is not detectable for PCCB with p.Arg514* (Sanchez-Alcudia_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Jun 22, 2021

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