NM_000532.5(PCCB):c.749A>G (p.His250Arg) AND Propionic acidemia

Clinical significance:Uncertain significance (Last evaluated: Mar 26, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001055500.3

Allele description [Variation Report for NM_000532.5(PCCB):c.749A>G (p.His250Arg)]

NM_000532.5(PCCB):c.749A>G (p.His250Arg)

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.749A>G (p.His250Arg)
HGVS:
  • NC_000003.12:g.136293850A>G
  • NG_008939.1:g.48526A>G
  • NM_000532.5:c.749A>GMANE SELECT
  • NM_001178014.1:c.809A>G
  • NP_000523.2:p.His250Arg
  • NP_001171485.1:p.His270Arg
  • NC_000003.11:g.136012692A>G
  • NM_000532.4:c.749A>G
Protein change:
H250R
Molecular consequence:
  • NM_000532.5:c.749A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178014.1:c.809A>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
SCV001219897Invitaecriteria provided, single submitter
Uncertain significance
(Mar 26, 2019)
germlineclinical testing

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

SCV001454519Natera, Inc.no assertion criteria providedUncertain significance
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV001219897.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces histidine with arginine at codon 250 of the PCCB protein (p.His250Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with propionic aciduria (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.His250 amino acid residue in PCCB. Other variant(s) that disrupt this residue have been observed in individuals with PCCB-related conditions (PMID: 30274917), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Natera, Inc., SCV001454519.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 27, 2021

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