3-136256586-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000532.5(PCCB):c.335G>A(p.Gly112Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G112S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PCCB
NM_000532.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 9.60

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

propionic acidemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health, Orphanet

PCCB links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-136256585-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1468741.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 61 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: -0.86701 (below the threshold of 3.09). Trascript score misZ: -0.97134 (below the threshold of 3.09). GenCC associations: The gene is linked to propionic acidemia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 3-136256586-G-A is Pathogenic according to our data. Variant chr3-136256586-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38883.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCB	NM_000532.5 link	c.335G>A	p.Gly112Asp	missense_variant	Exon 3 of 15	ENST00000251654.9	NP_000523.2	P05166-1
PCCB	NM_001178014.2 link	c.335G>A	p.Gly112Asp	missense_variant	Exon 3 of 16		NP_001171485.1	P05166-2
PCCB	XM_011512873.2 link	c.335G>A	p.Gly112Asp	missense_variant	Exon 3 of 11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 link	c.335G>A	p.Gly112Asp	missense_variant	Exon 3 of 15	1	NM_000532.5	ENSP00000251654.4		P05166-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Propionic acidemia

Pathogenic:1Other:1

Oct 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 112 of the PCCB protein (p.Gly112Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with propionic acidemia (PMID: 10910839, 29679984). ClinVar contains an entry for this variant (Variation ID: 38883). 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. Studies have shown that this missense change alters PCCB gene expression (PMID: 12757933). This variant disrupts the p.Gly112 amino acid residue in PCCB. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

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

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.8

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

PhyloP100

9.6

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.4

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

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.99

MutPred

0.94

Loss of methylation at R113 (P = 0.0278);Loss of methylation at R113 (P = 0.0278);Loss of methylation at R113 (P = 0.0278);Loss of methylation at R113 (P = 0.0278);Loss of methylation at R113 (P = 0.0278);Loss of methylation at R113 (P = 0.0278);Loss of methylation at R113 (P = 0.0278);.;Loss of methylation at R113 (P = 0.0278);.;.;

MVP

0.99

MPC

0.58

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.99

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over