NM_000532.5(PCCB):c.942C>A (p.Tyr314Ter) AND Propionic acidemia

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 20, 2020)

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:
RCV000341685.6

Allele description [Variation Report for NM_000532.5(PCCB):c.942C>A (p.Tyr314Ter)]

NM_000532.5(PCCB):c.942C>A (p.Tyr314Ter)

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.942C>A (p.Tyr314Ter)
Other names:
p.Y314*:TAC>TAA
HGVS:
  • NC_000003.12:g.136301087C>A
  • NG_008939.1:g.55763C>A
  • NM_000532.5:c.942C>AMANE SELECT
  • NM_001178014.1:c.1002C>A
  • NP_000523.2:p.Tyr314Ter
  • NP_001171485.1:p.Tyr334Ter
  • NC_000003.11:g.136019929C>A
  • NM_000532.4:c.942C>A
Protein change:
Y314*
Links:
dbSNP: rs572246667
NCBI 1000 Genomes Browser:
rs572246667
Molecular consequence:
  • NM_000532.5:c.942C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001178014.1:c.1002C>A - 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
SCV000800299Counsylcriteria provided, single submitter
Likely pathogenic
(Jun 4, 2018)
unknownclinical testing

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

Citation Link,

SCV001205750Invitaecriteria provided, single submitter
Pathogenic
(Aug 20, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001360762Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jun 3, 2019)
germlineclinical testing

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

Citation Link,

SCV001454522Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

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

Citations

PubMed

Propionic acidemia: mutation update and functional and structural effects of the variant alleles.

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

Mol Genet Metab. 2004 Sep-Oct;83(1-2):28-37. Review.

PubMed [citation]
PMID:
15464417

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000800299.1

#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, SCV001205750.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Tyr314*) in the PCCB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs572246667, ExAC 0.003%). This variant has been observed in an individual affected with propionic aciduria (PMID: 23430860). ClinVar contains an entry for this variant (Variation ID: 203882). Loss-of-function variants in PCCB 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360762.1

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

Description

Variant summary: PCCB c.942C>A (p.Tyr314X) 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 1.2e-05 in 251454 control chromosomes (gnomAD). The variant, c.942C>A, has been reported in the literature in individuals affected with Propionic Acidemia (Levesque_2011, Sanchez-Alcudia_2012). These data indicate that the variant may be associated with disease. At least one publication, Sanchez-Alcudia_2012, reports PCC activity of this variant from patients fibroblasts treated with readthrough drugs was <10% of normal activity. Three ClinVar submissions from clinical diagnostic laboratories (last evaluation after 2014) cite the variant as likely pathogenic/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

From Natera, Inc., SCV001454522.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 27, 2021

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