NM_000282.4(PCCA):c.1209+3A>G AND Propionic acidemia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 7, 2022
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:: RCV000668869.5

Allele description [Variation Report for NM_000282.4(PCCA):c.1209+3A>G]

NM_000282.4(PCCA):c.1209+3A>G

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.1209+3A>G

HGVS:

NC_000013.11:g.100301606A>G
NG_008768.1:g.217524A>G
NM_000282.4:c.1209+3A>GMANE SELECT
NM_001127692.3:c.1131+3A>G
NM_001178004.2:c.1209+3A>G
NM_001352605.2:c.1209+3A>G
NM_001352606.2:c.1066-1318A>G
NM_001352607.2:c.1131+3A>G
NM_001352608.2:c.988-1318A>G
NM_001352609.2:c.1209+3A>G
NM_001352610.2:c.264+3A>G
NM_001352611.2:c.264+3A>G
NM_001352612.2:c.121-1318A>G
NC_000013.10:g.100953860A>G
NM_000282.3:c.1209+3A>G

Links:

dbSNP: rs1467680142

NCBI 1000 Genomes Browser:

rs1467680142

Molecular consequence:

NM_000282.4:c.1209+3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001127692.3:c.1131+3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001178004.2:c.1209+3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001352605.2:c.1209+3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001352606.2:c.1066-1318A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001352607.2:c.1131+3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001352608.2:c.988-1318A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001352609.2:c.1209+3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001352610.2:c.264+3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001352611.2:c.264+3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001352612.2:c.121-1318A>G - intron variant - [Sequence Ontology: SO:0001627]

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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Methionine adenosyltransferase I, alpha [Mus musculus]
Methionine adenosyltransferase I, alpha [Mus musculus]
gi|15029956|gb|AAH11211.1|

Protein
Apolipoprotein F [Mus musculus]
Apolipoprotein F [Mus musculus]
gi|18605894|gb|AAH22795.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000793542	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Aug 18, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21094621, 17051315 Citation Link,
SCV001441003	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004296514	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 7, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 30274917, 17576681, 9536098, 21094621, 17051315, 22033733, 31319225, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000793542

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Aug 18, 2017)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001441003

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 1, 2019)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004296514

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 7, 2022)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

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	yes	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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000793542.1

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV001441003.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004296514.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change falls in intron 13 of the PCCA gene. It does not directly change the encoded amino acid sequence of the PCCA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PCCA protein in which other variant(s) (p.Arg399Trp) have been determined to be pathogenic (PMID: 30274917; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 13, but is expected to preserve the integrity of the reading-frame (PMID: 17051315, 21094621). ClinVar contains an entry for this variant (Variation ID: 553422). This variant has been observed in individuals with propionic acidemia (PMID: 17051315, 22033733, 31319225). This variant is present in population databases (no rsID available, gnomAD 0.0009%).

#	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 20, 2024

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