rs755776820

Positions:

• chr3-136262037-CTT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000532.5(PCCB):​c.517_518del​(p.Leu173GlyfsTer56) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,404,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PCCB NM_000532.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.850

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-136262037-CTT-C is Pathogenic according to our data. Variant chr3-136262037-CTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCB	NM_000532.5	c.517_518del	p.Leu173GlyfsTer56	frameshift_variant	5/15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2	c.577_578del	p.Leu193GlyfsTer56	frameshift_variant	6/16		NP_001171485.1
PCCB	XM_011512873.2	c.517_518del	p.Leu173GlyfsTer56	frameshift_variant	5/11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9	c.517_518del	p.Leu173GlyfsTer56	frameshift_variant	5/15	1	NM_000532.5	ENSP00000251654	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000183 AC: 3 AN: 163962 Hom.: 0 AF XY: 0.0000116 AC XY: 1 AN XY: 86152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1404032 Hom.: 0 AF XY: 0.00000144 AC XY: 1 AN XY: 692940

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000833

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Propionic acidemia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 03, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 29, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552452). This sequence change creates a premature translational stop signal (p.Leu173Glyfs*56) 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). This variant is present in population databases (rs755776820, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with propionic acidemia (PMID: 23430860). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2019

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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23430860) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs755776820; hg19: chr3-135980879;