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

gnomAD frequency: 0.00016  dbSNP: rs202247823

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790698	SCV000226231	pathogenic	not provided	2014-12-02	criteria provided, single submitter	clinical testing
Invitae	RCV000032130	SCV000756227	pathogenic	Propionic acidemia	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 536 of the PCCB protein (p.Asn536Asp). This variant is present in population databases (rs202247823, gnomAD 0.005%). This missense change has been observed in individuals with propionic acidemia (PMID: 12757933, 12888983, 22033733, 23053474, 28649556, 30013935). ClinVar contains an entry for this variant (Variation ID: 38881). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCCB protein function. Experimental studies have shown that this missense change affects PCCB function (PMID: 11136555, 12007220, 12757933, 22033733, 23053474). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000032130	SCV000915019	pathogenic	Propionic acidemia	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000032130	SCV000919958	pathogenic	Propionic acidemia	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.
Baylor Genetics	RCV000032130	SCV001162962	pathogenic	Propionic acidemia		criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000032130	SCV002073331	pathogenic	Propionic acidemia		criteria provided, single submitter	clinical testing	The missense variant p.N536D in PCCB (NM_000532.5) has been previously reported in affected individuals in homozygous and compound heterozygote state including patients of Amish origin, wherein it is a common variant (PerezCerda 2003; Kraus 2012; Scott Schwoerer J et al 2018). Functional studies detected a damaging effect (Perez-Cerda 2003; Kraus 2012). The variant has been submitted to ClinVar as Pathogenic. The p.N536D variant is observed in 5/1,13,620 (0.0044%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. In silico tools predict the variant to be damaging and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000032130	SCV003824777	pathogenic	Propionic acidemia	2024-01-18	criteria provided, single submitter	clinical testing
GeneReviews	RCV000032130	SCV000055686	not provided	Propionic acidemia		no assertion provided	literature only
Natera, Inc.	RCV000032130	SCV002081501	pathogenic	Propionic acidemia	2021-02-03	no assertion criteria provided	clinical testing