NM_000282.4(PCCA):c.1195C>T (p.Arg399Trp) AND Propionic acidemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 27, 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:: RCV000820501.8

Allele description [Variation Report for NM_000282.4(PCCA):c.1195C>T (p.Arg399Trp)]

NM_000282.4(PCCA):c.1195C>T (p.Arg399Trp)

Gene:

PCCA:propionyl-CoA carboxylase subunit alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q32.3

Genomic location:

Preferred name:

NM_000282.4(PCCA):c.1195C>T (p.Arg399Trp)

HGVS:

NC_000013.11:g.100301589C>T
NG_008768.1:g.217507C>T
NM_000282.4:c.1195C>TMANE SELECT
NM_001127692.3:c.1117C>T
NM_001178004.2:c.1195C>T
NM_001352605.2:c.1195C>T
NM_001352606.2:c.1066-1335C>T
NM_001352607.2:c.1117C>T
NM_001352608.2:c.988-1335C>T
NM_001352609.2:c.1195C>T
NM_001352610.2:c.250C>T
NM_001352611.2:c.250C>T
NM_001352612.2:c.121-1335C>T
NP_000273.2:p.Arg399Trp
NP_001121164.1:p.Arg373Trp
NP_001171475.1:p.Arg399Trp
NP_001339534.1:p.Arg399Trp
NP_001339536.1:p.Arg373Trp
NP_001339538.1:p.Arg399Trp
NP_001339539.1:p.Arg84Trp
NP_001339540.1:p.Arg84Trp
NC_000013.10:g.100953843C>T
NM_000282.3:c.1195C>T
NR_148027.2:n.1223C>T
NR_148028.2:n.1223C>T
NR_148029.2:n.1145C>T
NR_148030.2:n.1223C>T
NR_148031.2:n.1223C>T

Protein change:

R373W

Links:

dbSNP: rs1234167788

NCBI 1000 Genomes Browser:

rs1234167788

Molecular consequence:

NM_001352606.2:c.1066-1335C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001352608.2:c.988-1335C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001352612.2:c.121-1335C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000282.4:c.1195C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127692.3:c.1117C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178004.2:c.1195C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352605.2:c.1195C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352607.2:c.1117C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352609.2:c.1195C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352610.2:c.250C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352611.2:c.250C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148027.2:n.1223C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148028.2:n.1223C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148029.2:n.1145C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148030.2:n.1223C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148031.2:n.1223C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000961217	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30274917, 10518292, 28492532
SCV004202882	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000961217

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 27, 2023)

germline

clinical testing

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

SCV004202882

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 23, 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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of 34 novel mutations in propionic acidemia: Functional characterization of missense variants and phenotype associations.

Rivera-Barahona A, Navarrete R, García-Rodríguez R, Richard E, Ugarte M, Pérez-Cerda C, Pérez B, Gámez A, Desviat LR.

Mol Genet Metab. 2018 Nov;125(3):266-275. doi: 10.1016/j.ymgme.2018.09.008. Epub 2018 Sep 26.

PubMed [citation]

PMID:: 30274917

Mutation analysis of the propionyl-CoA carboxylase alpha-subunit gene in four Japanese patients with propionic acidaemia.

Ohura T, Narisawa K, Iinuma K.

J Inherit Metab Dis. 1999 Oct;22(7):851-2. No abstract available.

PubMed [citation]

PMID:: 10518292

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000961217.4

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 399 of the PCCA protein (p.Arg399Trp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with propionic acidemia (PMID: 30274917; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 662772). 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 PCCA protein function with a positive predictive value of 80%. This variant disrupts the p.Arg399 amino acid residue in PCCA. Other variant(s) that disrupt this residue have been observed in individuals with PCCA-related conditions (PMID: 10518292), 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 Baylor Genetics, SCV004202882.1

#	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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