rs111033542
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000532.5(PCCB):c.1283C>T(p.Thr428Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000532.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCCB | NM_000532.5 | c.1283C>T | p.Thr428Ile | missense_variant | 12/15 | ENST00000251654.9 | |
PCCB | NM_001178014.2 | c.1343C>T | p.Thr448Ile | missense_variant | 13/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCCB | ENST00000251654.9 | c.1283C>T | p.Thr428Ile | missense_variant | 12/15 | 1 | NM_000532.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251014Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135646
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461520Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727082
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Propionic acidemia Pathogenic:8Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 08, 2016 | Variant summary: The c.1283C>T (p.Tre428Ile) in PCCB gene is a missense change that alters a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant falls into the carboxyl-terminal portion of the b-subunit and mutations in this region are likely to diminish the ability of the mutant bPCC proteins to form PCC active oligomers. These predictions were also confirmed by functional studies, where no detectable enzymatic activities were found in fibroblasts of a patient homozygous T428I. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00002 (3/121052 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in PCCB gene (0.0025). The variant was found in multiple affected individuals with established dx of propionic acidemia. Kim (2002) and Ohura (1993) report the frequency of the variant of interest in affected individuals as 56.3% and 50%, respectively. Lastly, a reputable database/diagnostic center classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 15, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 02, 2018 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1993 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 428 of the PCCB protein (p.Thr428Ile). This variant is present in population databases (rs111033542, gnomAD 0.02%). This missense change has been observed in individual(s) with propionic acidemia (PMID: 8295402, 12409268). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12016). 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: 8852656). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 26, 2021 | The PCCB c.1283C>T, p.Thr428Ile variant (rs111033542) is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with propionic acidemia (Kim 2003, Yang 2004, Yorifugi 2002). This variant is also reported in ClinVar (Variation ID: 12016) and is found in the general population with an allele frequency of 0.002% (6/251014 alleles) in the Genome Aggregation Database. The threonine at codon 428 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.922). Based on available information, this variant is considered to be pathogenic. References: Kim SN et al. Molecular analysis of PCCB gene in Korean patients with propionic acidemia. Mol Genet Metab. 2002 Nov;77(3):209-16. PMID: 12409268. Yang X et al. Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia. Mol Genet Metab. 2004 Apr;81(4):335-42. PMID: 15059621. Yorifuji T et al. Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications. Hum Genet. 2002 Aug;111(2):161-5. PMID: 12189489. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at