3-136293784-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000532.5(PCCB):c.683C>T(p.Pro228Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,612,712 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P228A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000532.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCCB | NM_000532.5 | c.683C>T | p.Pro228Leu | missense_variant | 7/15 | ENST00000251654.9 | |
PCCB | NM_001178014.2 | c.743C>T | p.Pro248Leu | missense_variant | 8/16 | ||
PCCB | XM_011512873.2 | c.683C>T | p.Pro228Leu | missense_variant | 7/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCCB | ENST00000251654.9 | c.683C>T | p.Pro228Leu | missense_variant | 7/15 | 1 | NM_000532.5 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251268Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135796
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1460606Hom.: 0 Cov.: 29 AF XY: 0.0000661 AC XY: 48AN XY: 726700
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74294
ClinVar
Submissions by phenotype
Propionic acidemia Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 17, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 228 of the PCCB protein (p.Pro228Leu). This variant is present in population databases (rs374722096, gnomAD 0.01%). This missense change has been observed in individual(s) with propionic acidemia (PMID: 8023851, 12007220, 15949719; Invitae). ClinVar contains an entry for this variant (Variation ID: 198428). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PCCB function (PMID: 12007220). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 26, 2022 | Variant summary: PCCB c.683C>T (p.Pro228Leu) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251268 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PCCB causing Propionic Acidemia (4.8e-05 vs 0.0025), allowing no conclusion about variant significance. c.683C>T has been reported in the literature in individuals affected with Propionic Acidemia. These data indicate that the variant is likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 15, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 20, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 31, 2023 | Expression analysis of P228L found that this variant results in an increased alpha/beta subunit ratio compared to wild-type propionyl-CoA carboxylase indicating that P228L interferes with the correct assembly and/or subsequent stability of the assembled propionyl-CoA carboxylase holoenyzme (Chloupkova et al. 2002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27089410, 22033733, 25087612, 12007220, 7655456, 15890657, 30274917, 25047749, 31916709, 8023851, 15464417, 15949719, 27776753, 31589614, 36619936) - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 12, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2023 | The c.683C>T (p.P228L) alteration is located in exon 7 (coding exon 7) of the PCCB gene. This alteration results from a C to T substitution at nucleotide position 683, causing the proline (P) at amino acid position 228 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.006% (16/282662) total alleles studied. The highest observed frequency was 0.012% (16/128990) of European (non-Finnish) alleles. This alteration has been reported in a homozygous state and a compound heterozygous state with a second alteration in PCCB in multiple patients with features consistent with propionic acidemia (Gravel, 1994; Desviat, 2004; Kraus, 2012; Mungan, 2016; McCrory, 2017; Rivera-Barahona, 2018; Kör, 2019; Shchelochkov, 2019). This amino acid position is highly conserved in available vertebrate species. Functional studies suggest this alteration may alter PCC subunit assembly (Chloupkova, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at