NM_000532.5(PCCB):c.494G>A (p.Arg165Gln) AND Propionic acidemia

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Aug 13, 2024
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:: RCV000666130.12

Allele description [Variation Report for NM_000532.5(PCCB):c.494G>A (p.Arg165Gln)]

NM_000532.5(PCCB):c.494G>A (p.Arg165Gln)

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.494G>A (p.Arg165Gln)

HGVS:

NC_000003.12:g.136262016G>A
NG_008939.1:g.16692G>A
NM_000532.5:c.494G>AMANE SELECT
NM_001178014.2:c.554G>A
NP_000523.2:p.Arg165Gln
NP_001171485.1:p.Arg185Gln
NC_000003.11:g.135980858G>A
NM_000532.4:c.494G>A

Protein change:

R165Q

Links:

dbSNP: rs1304714042

NCBI 1000 Genomes Browser:

rs1304714042

Molecular consequence:

NM_000532.5:c.494G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178014.2:c.554G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000790374	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Mar 17, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15949719, 12757933 Citation Link,
SCV000941854	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8295402, 11749052, 12757933, 15949719, 20549364, 28492532
SCV003923312	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12757933, 25741868
SCV004205246	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 13, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005381141	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 13, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12559849, 11749052 Citation Link

Help

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Propionic acidaemia: sequence analysis of mutant mRNAs from Japanese beta subunit-deficient patients.

Ohura T, Narisawa K, Tada K.

J Inherit Metab Dis. 1993;16(5):863-7. No abstract available.

PubMed [citation]

PMID:: 8295402

Towards a model to explain the intragenic complementation in the heteromultimeric protein propionyl-CoA carboxylase.

Rodríguez-Pombo P, Pérez-Cerdá C, Pérez B, Desviat LR, Sánchez-Pulido L, Ugarte M.

Biochim Biophys Acta. 2005 Jun 10;1740(3):489-98. Epub 2004 Nov 2.

PubMed [citation]

PMID:: 15949719

See all PubMed Citations (8)

Details of each submission

From Counsyl, SCV000790374.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000941854.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 165 of the PCCB protein (p.Arg165Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with propionic acidemia (PMID: 11749052, 12757933). ClinVar contains an entry for this variant (Variation ID: 551146). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PCCB function (PMID: 12757933). This variant disrupts the p.Arg165 amino acid residue in PCCB. Other variant(s) that disrupt this residue have been observed in individuals with PCCB-related conditions (PMID: 8295402, 11749052, 12757933, 15949719, 20549364), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	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 Lifecell International Pvt. Ltd, SCV003923312.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

A Homozygote Missense variant c.494G>A in Exon 5 of the PCCB gene that results in the amino acid substitution p.Arg165Gln was identified. The observed variant has a maximum allele frequency of 0.00001/0.00 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (ClinVar ID: 551146). This variant has previously been reported for Propionic acidemia by Stanescu S et al., 2021. Furthermore, functional studies demonstrate that this variant has a damaging effect on the gene or gene product (Pérez-Cerdá C et al., 2003). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

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

From Baylor Genetics, SCV004205246.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005381141.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: PCCB c.494G>A (p.Arg165Gln) results in a conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.9e-06 in 169706 control chromosomes (gnomAD). c.494G>A has been reported in the literature in individuals affected with Propionic Acidemia (e.g. Muro_2001, Perez-Cerda_2003). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.493C>T, p.Arg165Trp), supporting the critical relevance of codon 165 to PCCB protein function. At least one publication reports experimental evidence evaluating an impact on enzymatic function, finding that the variant results in <1% of wild type PCC activity (Perez-Cerda_2003). The following publications have been ascertained in the context of this evaluation (PMID: 11749052, 12559849). ClinVar contains an entry for this variant (Variation ID: 551146). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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

Last Updated: Oct 26, 2024

ClinVar

Relating variation to medicine