NM_000532.5(PCCB):c.562G>A (p.Gly188Arg) AND Propionic acidemia

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 4, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000674578.3

Allele description [Variation Report for NM_000532.5(PCCB):c.562G>A (p.Gly188Arg)]

NM_000532.5(PCCB):c.562G>A (p.Gly188Arg)

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.562G>A (p.Gly188Arg)
HGVS:
  • NC_000003.12:g.136283855G>A
  • NG_008939.1:g.38531G>A
  • NM_000532.5:c.562G>AMANE SELECT
  • NM_001178014.1:c.622G>A
  • NP_000523.2:p.Gly188Arg
  • NP_001171485.1:p.Gly208Arg
  • NC_000003.11:g.136002697G>A
  • NM_000532.4:c.562G>A
Protein change:
G188R
Links:
dbSNP: rs746102997
NCBI 1000 Genomes Browser:
rs746102997
Molecular consequence:
  • NM_000532.5:c.562G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178014.1:c.622G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000799938Counsylcriteria provided, single submitter
Likely pathogenic
(May 14, 2018)
unknownclinical testing

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

Citation Link,

SCV000961644Invitaecriteria provided, single submitter
Likely pathogenic
(Oct 30, 2018)
germlineclinical testing

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

SCV001360763Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Oct 4, 2019)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

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

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

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
See all PubMed Citations (10)

Details of each submission

From Counsyl, SCV000799938.1

#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, SCV000961644.1

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

Description

This sequence change replaces glycine with arginine at codon 188 of the PCCB protein (p.Gly188Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs746102997, ExAC 0.01%). This variant has been observed in individuals affected with propionic acidemia (PMID: 12559849, 22033733, 23053474, 27900673). ClinVar contains an entry for this variant (Variation ID: 558327). Experimental studies have shown that this missense change impairs enzymatic activity (PMID: 23053474). 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360763.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: PCCB c.562G>A (p.Gly188Arg) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251438 control chromosomes (gnomAD). c.562G>A has been reported in the literature in multiple individuals (compound heterozygotes or homozygotes) affected with Propionic Acidemia (Perez_2003, Desviat_2006, Kraus_2012, Gallego-Villar_2012, Cappuccio_2016, Tummolo_2018). These data indicate that the variant is very likely to be associated with disease. In vitro study showed that this variant had residual activity at 13% of WT levels (Gallego-Villar_2012). Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as 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 14, 2021

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