rs202247823

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 8.60

Variant links:

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]

PCCB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
PCCB	NM_000532.5 link	c.1606A>G	p.Asn536Asp	missense_variant	Exon 15 of 15	ENST00000251654.9	NP_000523.2	P05166-1
PCCB	NM_001178014.2 link	c.1666A>G	p.Asn556Asp	missense_variant	Exon 16 of 16		NP_001171485.1	P05166-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 link	c.1606A>G	p.Asn536Asp	missense_variant	Exon 15 of 15	1	NM_000532.5	ENSP00000251654.4		P05166-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

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:

AN:

251308

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135818

show subpopulations

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:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727226

show subpopulations

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:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74368

show subpopulations

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.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Propionic acidemia

Pathogenic:8Other:1

Aug 23, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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, PÃ©rez-CerdÃ¡ 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. PÃ©rez-CerdÃ¡ 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. -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence 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 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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 05, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 25, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.1606A>G (p.Asn536Asp) in PCCB gene has been observed in homozygous state in multiple individuals with propionic acidemia (Wenger et. al., 2020; Scott Schwoerer et. al., 2018). Experimental studies have shown that this missense change affects PCCB function (Gallego-Villaret. et. al., 2013). The p.Asn536Asp variant is present with allele frequency of 0.002% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on PCCB gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 536 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. The above variant in PCCB gene has also been detected in homozygous state in brother. -

Feb 03, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Dec 02, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PCCB-related disorder

Pathogenic:1

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PCCB c.1606A>G variant is predicted to result in the amino acid substitution p.Asn536Asp. This variant has been commonly reported to be causative for propionic acidemia (Gravel et al. 1994. PubMed ID: 8023851; Kraus et al. 2012. PubMed ID: 22033733; Schwoerer et al. 2018. PubMed ID: 30013935; Stanescu et al. 2021. PubMed ID: 33473339). In vitro studies have shown that the p.Asn536Asp substitution results in a PCC enzyme with moderate residual activity, which is consistent with the finding that the c.1606A>G variant is often associated with a milder phenotype (Pérez-Cerdá et al. 2003. PubMed ID: 12757933). Although the p.Asn563 amino acid is located in the C-terminus of the PCCB protein only three amino acids from the protein termination codon, studies have shown that the p.Asn536Asp substitution affects protein subunit association (Muro et al. 2001. PubMed ID: 11749052; Desviat et al. 2004. PubMed ID: 15464417). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

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

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Uncertain

0.44

T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.65

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over