3-136262016-G-C

Variant names:

• chr3-136262016-G-C
• rs1304714042
• NM_000532.5:c.494G>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000532.5(PCCB):​c.494G>C​(p.Arg165Pro) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.50
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 chr3-136262016-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 551146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.973
• PP5: Variant 3-136262016-G-C is Pathogenic according to our data. Variant chr3-136262016-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2677518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCB	NM_000532.5	c.494G>C	p.Arg165Pro	missense_variant	Exon 5 of 15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2	c.554G>C	p.Arg185Pro	missense_variant	Exon 6 of 16		NP_001171485.1
PCCB	XM_011512873.2	c.494G>C	p.Arg165Pro	missense_variant	Exon 5 of 11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9	c.494G>C	p.Arg165Pro	missense_variant	Exon 5 of 15	1	NM_000532.5	ENSP00000251654.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Propionic acidemia Pathogenic:3

Jun 17, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg165 amino acid residue in PCCB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11749052, 12757933). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PCCB function (PMID: 20549364). 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) performed at Invitae indicates that this missense variant is expected to disrupt PCCB protein function. This missense change has been observed in individual(s) with propionic acidemia (PMID: 20549364). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 165 of the PCCB protein (p.Arg165Pro). -

Aug 22, 2024

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.494G>C (p.Arg165Pro) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 169706 control chromosomes. c.494G>C has been reported in the literature in the presumed compound heterozygous state in at least 1 individual affected with Propionic Acidemia (example, Perez_2010). Two different variants affecting the same codon have been classified as pathogenic by our lab (c.493C>T, p.Arg165Trp and c.494G>A, p.Arg165Gln), supporting the critical relevance of codon 165 to PCCB protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example, Perez_2010). The following publication has been ascertained in the context of this evaluation (PMID: 20549364). ClinVar contains an entry for this variant (Variation ID: 2677518). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;D;D;.;.;.;D;D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H;.;.;.;.;.;.;.;.;.;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.3	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	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		0.96
MutPred		0.84		Gain of disorder (P = 0.1297);.;.;.;Gain of disorder (P = 0.1297);.;Gain of disorder (P = 0.1297);.;Gain of disorder (P = 0.1297);.;.;
MVP		0.98
MPC		0.62
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.95
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs1304714042; hg19: chr3-135980858;