rs202247823

chr3-136330012-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000532.5(PCCB):c.1606A>G(p.Asn536Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 8.60

Genes affected

PCCB (HGNC:8654): (propionyl-CoA carboxylase subunit beta) The protein encoded by this gene is a subunit of the propionyl-CoA carboxylase (PCC) enzyme, which is involved in the catabolism of propionyl-CoA. PCC is a mitochondrial enzyme that probably acts as a dodecamer of six alpha subunits and six beta subunits. This gene encodes the beta subunit of PCC. Defects in this gene are a cause of propionic acidemia type II (PA-2). Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-136330012-A-G is Pathogenic according to our data. Variant chr3-136330012-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 38881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-136330012-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCB	NM_000532.5	c.1606A>G	p.Asn536Asp	missense_variant	15/15	ENST00000251654.9
PCCB	NM_001178014.2	c.1666A>G	p.Asn556Asp	missense_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCB	ENST00000251654.9	c.1606A>G	p.Asn536Asp	missense_variant	15/15	1	NM_000532.5	P2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251308 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Propionic acidemia Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2018	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 23, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;D;D;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.4	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.87
MVP		0.97
MPC		0.55
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202247823; hg19: chr3-136048854; COSMIC: COSV52449094; COSMIC: COSV52449094;