rs778742647

Variant names:

• chr3-136327185-G-A
• rs778742647
• NM_000532.5:c.1229G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_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 Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 9.50
• Publications: 3 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 17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr3-136327184-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12011.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, 0.9
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCB	NM_000532.5	c.1229G>A	p.Arg410Gln	missense_variant	Exon 12 of 15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2	c.1289G>A	p.Arg430Gln	missense_variant	Exon 13 of 16		NP_001171485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9	c.1229G>A	p.Arg410Gln	missense_variant	Exon 12 of 15	1	NM_000532.5	ENSP00000251654.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152124 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 251060 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727238

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74302

African (AFR) AF: 0.0000483 AC: 2 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000719 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Propionic acidemia Pathogenic:5 Uncertain:1

Feb 24, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. 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. -

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 15, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jun 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
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	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.;.;.;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.87	D
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	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.85
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs778742647; hg19: chr3-136046027; COSMIC: COSV52443873; COSMIC: COSV52443873;