rs1304714042
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000532.5(PCCB):c.494G>A(p.Arg165Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000355 in 1,408,544 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000532.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.494G>A | p.Arg165Gln | missense_variant | 5/15 | ENST00000251654.9 | |
PCCB | NM_001178014.2 | c.554G>A | p.Arg185Gln | missense_variant | 6/16 | ||
PCCB | XM_011512873.2 | c.494G>A | p.Arg165Gln | missense_variant | 5/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCCB | ENST00000251654.9 | c.494G>A | p.Arg165Gln | missense_variant | 5/15 | 1 | NM_000532.5 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000589 AC: 1AN: 169706Hom.: 0 AF XY: 0.0000112 AC XY: 1AN XY: 89308
GnomAD4 exome AF: 0.00000355 AC: 5AN: 1408544Hom.: 0 Cov.: 30 AF XY: 0.00000288 AC XY: 2AN XY: 695426
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Propionic acidemia Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 13, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 165 of the PCCB protein (p.Arg165Gln). 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 missense change has been observed in individuals with propionic acidemia (PMID: 11749052, 12757933). ClinVar contains an entry for this variant (Variation ID: 551146). 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: 12757933). This variant disrupts the p.Arg165 amino acid residue in PCCB. Other variant(s) that disrupt this residue have been observed in individuals with PCCB-related conditions (PMID: 8295402, 11749052, 12757933, 15949719, 20549364), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Homozygote Missense variant c.494G>A in Exon 5 of the PCCB gene that results in the amino acid substitution p.Arg165Gln was identified. The observed variant has a maximum allele frequency of 0.00001/0.00 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (ClinVar ID: 551146). This variant has previously been reported for Propionic acidemia by Stanescu S et al., 2021. Furthermore, functional studies demonstrate that this variant has a damaging effect on the gene or gene product (Pérez-Cerdá C et al., 2003). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at