rs202247821

Variant names:

• chr3-136329943-G-GCCC
• rs202247821
• NM_000532.5:c.1538_1540dupCCC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_000532.5(PCCB):​c.1538_1540dupCCC​(p.Ala513_Arg514insPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R514R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCCB NM_000532.5 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.71
• Publications: 1 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: Likely_pathogenic. The variant received 7 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, 6 uncertain in NM_000532.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000532.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-136329943-G-GCCC is Pathogenic according to our data. Variant chr3-136329943-G-GCCC is described in ClinVar as Pathogenic. ClinVar VariationId is 12017.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	c.1538_1540dupCCC	p.Ala513_Arg514insPro	disruptive_inframe_insertion	Exon 15 of 15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2	c.1598_1600dupCCC	p.Ala533_Arg534insPro	disruptive_inframe_insertion	Exon 16 of 16		NP_001171485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9	c.1538_1540dupCCC	p.Ala513_Arg514insPro	disruptive_inframe_insertion	Exon 15 of 15	1	NM_000532.5	ENSP00000251654.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Propionic acidemia Pathogenic:2 Other:1

Jul 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 27, 2025

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.1538_1540dupCCC (p.Ala513_Arg514insPro) results in an in-frame insertion that is predicted to insert one amino acid into the encoded protein. The variant was absent in 251258 control chromosomes. c.1538_1540dupCCC has been reported in the literature in the homozygous state in multiple individuals affected with Propionic Acidemia (Ravn_2000). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing that this variant results in absent PCC activity in e. coli (Ravn_2000). The following publication have been ascertained in the context of this evaluation (PMID: 10820128). ClinVar contains an entry for this variant (Variation ID: 12017). Based on the evidence outlined above, the variant was classified as pathogenic. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=62/38	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs202247821; hg19: chr3-136048785;