NM_000532.5(PCCB):c.1556T>C (p.Leu519Pro) AND Propionic acidemia

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 21, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000032129.11

Allele description [Variation Report for NM_000532.5(PCCB):c.1556T>C (p.Leu519Pro)]

NM_000532.5(PCCB):c.1556T>C (p.Leu519Pro)

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.1556T>C (p.Leu519Pro)

HGVS:

NC_000003.12:g.136329962T>C
NG_008939.1:g.84638T>C
NM_000532.5:c.1556T>CMANE SELECT
NM_001178014.2:c.1616T>C
NP_000523.2:p.Leu519Pro
NP_001171485.1:p.Leu539Pro
NC_000003.11:g.136048804T>C
NM_000532.4:c.1556T>C
P05166:p.Leu519Pro

Protein change:

L519P

Links:

UniProtKB: P05166#VAR_000281; dbSNP: rs202247822

NCBI 1000 Genomes Browser:

rs202247822

Molecular consequence:

NM_000532.5:c.1556T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001178014.2:c.1616T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Propionic acidemia (PROP)
Synonyms:: Glycinemia, ketotic; Hyperglycinemia with ketoacidosis and leukopenia; Ketotic hyperglycinemia
Identifiers:: MONDO: MONDO:0011628; MedGen: C0268579; Orphanet: 35; OMIM: 606054; Human Phenotype Ontology: HP:0003571

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000055685	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (1) [See all records that cite this PMID]
SCV002244425	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 27, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11749052, 12007220, 15949719, 12757933, 28492532
SCV002790124	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 3, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004205234	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 21, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Propionic Acidemia..

Galarreta Aima CI, Shchelochkov OA, Jerves Serrano T, Venditti CP.

2012 May 17 [updated 2024 Sep 26]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 22593918

Effect of PCCB gene mutations on the heteromeric and homomeric assembly of propionyl-CoA carboxylase.

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

Mol Genet Metab. 2001 Dec;74(4):476-83.

PubMed [citation]

PMID:: 11749052

See all PubMed Citations (7)

Details of each submission

From GeneReviews, SCV000055685.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002244425.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PCCB function (PMID: 11749052, 12007220, 12757933, 15949719). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCCB protein function. ClinVar contains an entry for this variant (Variation ID: 38880). This missense change has been observed in individual(s) with propionic acidemia (PMID: 12757933). This variant is present in population databases (rs202247822, gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 519 of the PCCB protein (p.Leu519Pro).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002790124.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004205234.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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