rs778742647

Positions:

chr3-136327185-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000532.5(PCCB):c.1229G>A(p.Arg410Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R410W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PCCB
NM_000532.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 9.50

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 16 ACMG points.

PM1

In a domain CoA carboxyltransferase C-terminal (size 239) in uniprot entity PCCB_HUMAN there are 29 pathogenic changes around while only 1 benign (97%) in NM_000532.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-136327184-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.9

PP5

Variant 3-136327185-G-A is Pathogenic according to our data. Variant chr3-136327185-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-136327185-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCB	NM_000532.5 link	c.1229G>A	p.Arg410Gln	missense_variant	12/15	ENST00000251654.9	NP_000523.2	P05166-1
PCCB	NM_001178014.2 link	c.1289G>A	p.Arg430Gln	missense_variant	13/16		NP_001171485.1	P05166-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 link	c.1229G>A	p.Arg410Gln	missense_variant	12/15	1	NM_000532.5	ENSP00000251654.4		P05166-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

251060

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Propionic acidemia

Pathogenic:5Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2024	The p.Arg430Gln variant in PCCB has been reported in the homozygous and compound heterozygous state in 2 individuals with propionic acidemia (Lee 2009 PMID: 19238581, Laemmle 2014 PMID: 24916042). These individuals had low levels of enzyme activity. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 557302) and has been identified in 0.02% (1/5200) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Another variant involving this codon (p.Arg430Trp) has been identified in individuals with propionic acidemia and has been classified as pathogenic by multiple clinical laboratories in ClinVar. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive propionic acidemia. ACMG/AMP Criteria applied: PM3, PM5, PP4, PM2_Supporting, PP3. -
Uncertain significance, flagged submission	clinical testing	Counsyl	Mar 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 05, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 410 of the PCCB protein (p.Arg410Gln). This variant is present in population databases (rs778742647, gnomAD 0.03%). This missense change has been observed in individual(s) with propionic acidemia (PMID: 19238581, 24916042). ClinVar contains an entry for this variant (Variation ID: 557302). 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. This variant disrupts the p.Arg410 amino acid residue in PCCB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8411997, 12007220, 12757933, 15890657, 15949719, 22033733). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 20, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 24, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;D;D;D;.;.;.

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

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

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.90

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.7

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

REVEL

Pathogenic

0.94

Sift

Benign

0.045

D;D;D;D;D;D;T;D;D

Sift4G

Uncertain

0.010

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

Polyphen

1.0

D;.;.;.;.;.;.;D;.

Vest4

0.94

MutPred

0.80

Loss of methylation at R410 (P = 0.071);.;.;.;.;.;.;Loss of methylation at R410 (P = 0.071);.;

MVP

0.97

MPC

0.53

ClinPred

0.83

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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