NM_000532.5(PCCB):c.1316A>G (p.Tyr439Cys) AND Propionic acidemia

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 24, 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:: RCV000490483.7

Allele description [Variation Report for NM_000532.5(PCCB):c.1316A>G (p.Tyr439Cys)]

NM_000532.5(PCCB):c.1316A>G (p.Tyr439Cys)

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.1316A>G (p.Tyr439Cys)

HGVS:

NC_000003.12:g.136327650A>G
NG_008939.1:g.82326A>G
NM_000532.5:c.1316A>GMANE SELECT
NM_001178014.2:c.1376A>G
NP_000523.2:p.Tyr439Cys
NP_001171485.1:p.Tyr459Cys
NC_000003.11:g.136046492A>G
NM_000532.4:c.1316A>G

Protein change:

Y439C

Links:

dbSNP: rs769521436

NCBI 1000 Genomes Browser:

rs769521436

Molecular consequence:

NM_000532.5:c.1316A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001178014.2:c.1376A>G - 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
SCV000267437	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 18, 2016)	germline	reference population	PubMed (3) [See all records that cite these PMIDs] 12189489, 12409268, 25741868
SCV000792715	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jul 20, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24863100, 12409268, 12189489 Citation Link,
SCV000919959	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 7, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27578510, 12409268, 24863100, 15464417 Citation Link,
SCV001580904	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12189489, 12409268, 31808324, 28492532
SCV004205204	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 8, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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
East Asian	germline	unknown	1	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

A Population-Based Genomic Study of Inherited Metabolic Diseases Detected Through Newborn Screening.

Park KJ, Park S, Lee E, Park JH, Park JH, Park HD, Lee SY, Kim JW.

Ann Lab Med. 2016 Nov;36(6):561-72. doi: 10.3343/alm.2016.36.6.561.

PubMed [citation]

PMID:: 27578510
PMCID:: PMC5011110

Two frequent mutations associated with the classic form of propionic acidemia in Taiwan.

Chiu YH, Liu YN, Liao WL, Chang YC, Lin SP, Hsu CC, Chiu PC, Niu DM, Wang CH, Ke YY, Chien YH, Hsiao KJ, Liu TT.

Biochem Genet. 2014 Oct;52(9-10):415-29. doi: 10.1007/s10528-014-9657-6. Epub 2014 May 27.

PubMed [citation]

PMID:: 24863100

See all PubMed Citations (8)

Details of each submission

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267437.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	1	not provided	not provided	reference population	PubMed (3)

#	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		1	not provided	not provided	not provided

From Counsyl, SCV000792715.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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, SCV000919959.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: PCCB c.1316A>G (p.Tyr439Cys) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) 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 2e-05 in 246228 control chromosomes, mostly occuring in the East Asian subpopulation. c.1316A>G has been reported in the literature in individuals affected with Propionic Acidemia; all of these cases were found in East Asian populations (Kim 2002, Yorifuji 2002, Chiu 2014). These data indicate that the variant is likely to be associated with disease. These publications also reported a significantly decreased enzyme activity in the affected individuals, with the most pronounced variant effect resulting in <10% of normal activity. A recent population study demonstrated a founder effect for the variant in the Korean population based on haplotype analysis (Park 2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. 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

From Invitae, SCV001580904.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 439 of the PCCB protein (p.Tyr439Cys). This variant is present in population databases (rs769521436, gnomAD 0.02%). This missense change has been observed in individual(s) with PCCB-related conditions (PMID: 12189489, 12409268, 31808324). ClinVar contains an entry for this variant (Variation ID: 225429). 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%. 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 Baylor Genetics, SCV004205204.1

#	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: Feb 20, 2024

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