11-66870399-C-T
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_001040716.2(PC):c.806G>A(p.Arg269Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,476 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
PC
NM_001040716.2 missense
NM_001040716.2 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 7.59
Genes affected
PC (HGNC:8636): (pyruvate carboxylase) This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Mutations in this gene have been associated with pyruvate carboxylase deficiency. Alternatively spliced transcript variants with different 5' UTRs, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a domain ATP-grasp (size 197) in uniprot entity PYC_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001040716.2
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 11-66870399-C-T is Pathogenic according to our data. Variant chr11-66870399-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550614.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=3}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PC | NM_001040716.2 | c.806G>A | p.Arg269Gln | missense_variant | Exon 9 of 23 | ENST00000393960.7 | NP_001035806.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250722Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135656
GnomAD3 exomes
AF:
AC:
2
AN:
250722
Hom.:
AF XY:
AC XY:
2
AN XY:
135656
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461476Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727076
GnomAD4 exome
AF:
AC:
11
AN:
1461476
Hom.:
Cov.:
32
AF XY:
AC XY:
5
AN XY:
727076
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Pyruvate carboxylase deficiency Pathogenic:4Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed missense c.806G>A(p.Arg269Gln) variant in PC gene has been reported previously in homozygous state in individuals affected with pyruvate carboxylase deficiency (Wang D, et al., 2008; Bayat R, et al., 2021). The p.Arg269Gln variant has been reported with allele frequency of 0.0008% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic. The amino acid change p.Arg269Gln in PC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 269 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 28, 2025 | Variant summary: PC c.806G>A (p.Arg269Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250722 control chromosomes. c.806G>A has been reported in the literature in bi-allelic individuals affected with Pyruvate Carboxylase Deficiency Type A and B, with PC activity in cultured skin fibroblasts below reference range (examples: Wang_2008 and Lasio_2023). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18676167, 37207470). ClinVar contains an entry for this variant (Variation ID: 550614). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 03, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 23, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 269 of the PC protein (p.Arg269Gln). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with pyruvate carboxylase deficiency (PMID: 18676167). ClinVar contains an entry for this variant (Variation ID: 550614). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;.
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;D;D;.;.
Vest4
MutPred
Loss of catalytic residue at R269 (P = 0.0028);Loss of catalytic residue at R269 (P = 0.0028);Loss of catalytic residue at R269 (P = 0.0028);.;.;
MVP
MPC
2.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at