rs397507445

Variant names:

• chr3-136327174-GGGCATCATCCGGC-TAGAGCACAGGA
• rs397507445
• NM_000532.5:c.1218_1231delGGGCATCATCCGGCinsTAGAGCACAGGA

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PS1 PM2 PP5_Very_Strong

The NM_000532.5(PCCB):​c.1218_1231delGGGCATCATCCGGCinsTAGAGCACAGGA​(p.Gly407ArgfsTer14) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCCB NM_000532.5 frameshift, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.50

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]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS1: Transcript NM_000532.5 (PCCB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-136327174-GGGCATCATCCGGC-TAGAGCACAGGA is Pathogenic according to our data. Variant chr3-136327174-GGGCATCATCCGGC-TAGAGCACAGGA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38875.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.1218_1231delGGGCATCATCCGGCinsTAGAGCACAGGA	p.Gly407ArgfsTer14	frameshift_variant, missense_variant	Exon 12 of 15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2	c.1278_1291delGGGCATCATCCGGCinsTAGAGCACAGGA	p.Gly427ArgfsTer14	frameshift_variant, 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.1218_1231delGGGCATCATCCGGCinsTAGAGCACAGGA	p.Gly407ArgfsTer14	frameshift_variant, missense_variant	Exon 12 of 15	1	NM_000532.5	ENSP00000251654.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Propionic acidemia Pathogenic:8

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000532.4(PCCB):c.1218_1231del14ins12(G407Rfs*14) is classified as pathogenic in the context of PCCB-related propionic acidemia. Sources cited for classification include the following: PMID 20549364. Classification NM_000532.4(PCCB):c.1218_1231del14ins12(G407Rfs*14) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

May 17, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Aug 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly407Argfs*14) in the PCCB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCCB are known to be pathogenic (PMID: 15464417). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with propionic acidemia (PMID: 2249848, 9683601). It is commonly reported in individuals of European and South American ancestry (PMID: 15464417). This variant is also known as c.1218del14ins12. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 21, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: This c.1218_1231delinsTAGAGCACAGGA (or c.1218_1231del14ins12) variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 407 and leads to a premature termination codon 14 amino acids downstream. It is predicted to cause a truncated or absent PCCB protein. Loss-of-function due to mutations in this gene is an established disease mechanism in Propionic Acidemia. This variant was not found in approximately 121298 controls chromosomes (including broad and large populations of ExAC). In literature and databases, this variant has been reported or found as the most common pathogenic variant in Caucasians that causes Propionic Acidemia. One clinical lab and multiple databases have classified this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic. -

Dec 24, 2023

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2023

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2024

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Oct 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21125326, 8023851, 30094188, 2154743, 33473339) -

Dec 14, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCCB: PM3:Very Strong, PVS1, PM2, PP4 -

Inborn genetic diseases Pathogenic:1

Jan 05, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1218_1231delinsTAGAGCACAGGA (p.G407Rfs*14) alteration, located in exon 12 (coding exon 12) of the PCCB gene, consists of a deletion of 14 and insertion of 12 nucleotides causing a translational frameshift at position 1218 with a predicted alternate stop codon after 14 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the available evidence, this alteration is classified as pathogenic. -

PCCB-related disorder Pathogenic:1

Sep 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PCCB c.1218_1231delinsTAGAGCACAGGA variant is predicted to result in a frameshift and premature protein termination (p.Gly407Argfs*14). This variant has been reported in individuals with propionic acidemia (Tahara et al. 1990. PubMed ID: 2154743; Alberola et al. 2010. PubMed ID: 21125326; Sambuughin et al. 2018. PubMed ID: 30094188; Gravel et al. 1994. PubMed ID: 8023851). This particular variant is a prevalent pathogenic variant in European and Latin American populations (Rodríguez-Pombo et al. 1998. PubMed ID: 9683601; Desviat et al. 2004. PubMed ID: 15464417; Kraus et al. 2012. PubMed ID: 22033733). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PCCB are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397507445; hg19: chr3-136046016;