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

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 7, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000490483.3

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_001178014.1: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_001178014.1:c.1376A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Propionic acidemia (PROP)
Synonyms:
Propionyl-CoA carboxylase deficiency; PCC deficiency; Glycinemia, ketotic; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0011628; MedGen: C0268579; Orphanet: 35; OMIM: 606054; Human Phenotype Ontology: HP:0003353

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000267437Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Centercriteria provided, single submitter
Likely pathogenic
(Mar 18, 2016)
germlinereference population

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

SCV000792715Counsylcriteria provided, single submitter
Likely pathogenic
(Jul 20, 2017)
unknownclinical testing

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

Citation Link,

SCV000919959Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jun 7, 2018)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001580904Invitaecriteria provided, single submitter
Pathogenic
(Oct 7, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
East Asiangermlineunknown1not providednot providednot providednot providedreference population

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

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
See all PubMed Citations (8)

Details of each submission

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1East Asian1not providednot providedreference population PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From Counsyl, SCV000792715.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919959.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001580904.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces tyrosine with cysteine at codon 439 of the PCCB protein (p.Tyr439Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs769521436, ExAC 0.02%). This variant 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. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 14, 2021

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