ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.1606A>G (p.Asn536Asp) (rs202247823)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790698 SCV000226231 pathogenic not provided 2014-12-02 criteria provided, single submitter clinical testing
GeneReviews RCV000032130 SCV000055686 pathologic Propionyl-CoA carboxylase deficiency 2012-05-17 no assertion criteria provided curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000032130 SCV000915019 pathogenic Propionyl-CoA carboxylase deficiency 2018-08-23 criteria provided, single submitter clinical testing The PCCB c.1606A>G (p.Asn536Asp) missense variant, also referred to as c.1666A>G (p.Asn556Asp), was reported in one homozygote and five compound heterozygotes with propionic acidemia (Gravel et al. 1994, Pérez-Cerdá et al. 2003, Kraus J et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.000047 in the European (non-Finnish) population of the Genome Aggregation Database. Pérez-Cerdá et al. (2003) demonstrated the p.Asn556Asp variant exhibited propionyl-CoA carboxylase activity at 80% of wild type in transfected fibroblast cell lines but stable protein production by northern and western blot analysis, which is consistent with the mild phenotype reported in observed probands. Based on the evidence the p.Asn556Asp variant is classified as pathogenic for propionic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000032130 SCV000919958 pathogenic Propionyl-CoA carboxylase deficiency 2018-02-05 criteria provided, single submitter clinical testing Variant summary: PCCB c.1606A>G (p.Asn536Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 277058 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PCCB causing Propionic Acidemia (2.2e-05 vs 0.0025), allowing no conclusion about variant significance. The c.1606A>G variant has been reported in the literature in multiple individuals affected with Propionic Acidemia (Gravel 1994, Perez-Cerda 2003, Kraus 2012). These data indicate that the variant is very likely to be associated with disease. Functional studies also reported experimental evidence that the variant has an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Gravel 1994, Perez-Cerda 2003, Kraus 2012). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000032130 SCV000756227 likely pathogenic Propionyl-CoA carboxylase deficiency 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 536 of the PCCB protein (p.Asn536Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs202247823, ExAC 0.001%). This variant has been reported in several individuals affected with propionic acidemia (PMID: 22033733, 23053474), including one homozygous individual (PMID: 12757933). It has been suggested to be a common variant in the Old Order Amish and Mennonite communities (PMID: 12888983, 28649556). ClinVar contains an entry for this variant (Variation ID: 38881). Experimental studies have shown that this missense change results in destabilization of the PCCB protein in prokaryotic cells (PMID: 11136555, 12007220). In contrast, in eukaryotic cells the protein is properly expressed, but only has 80% of wild-type protein activity (PMID: 12757933, 23053474). Cells derived from an individual who was homozygous for this variant had 14% of wild-type enzyme activity (PMID: 12757933), while other individuals who were heterozygous for this variant and a loss-of-function variant had <1% residual enzyme activity (PMID: 22033733). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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