Variant summary: PCCB c.502G>A (p.Glu168Lys) results in a conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of 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 6e-06 in 166868 control chromosomes. c.502G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Propionic Acidemia (example, Rodriguez-Pombo_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Perez-Cedra_2003). The most pronounced variant effect results in undetectable levels (approximately 1%) of normal propionyl-CoA carboxylase (PCC) enzyme activity in vitro. Three 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.
ClinVar Genomic variation as it relates to human health
NM_000532.5(PCCB):c.502G>A (p.Glu168Lys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000532.5(PCCB):c.502G>A (p.Glu168Lys)
Variation ID: 12015 Accession: VCV000012015.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q22.3 3: 136262024 (GRCh38) [ NCBI UCSC ] 3: 135980866 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Jun 17, 2024 Feb 26, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000532.5:c.502G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000523.2:p.Glu168Lys missense NM_001178014.2:c.562G>A NP_001171485.1:p.Glu188Lys missense NC_000003.12:g.136262024G>A NC_000003.11:g.135980866G>A NG_008939.1:g.16700G>A P05166:p.Glu168Lys - Protein change
- E168K, E188K
- Other names
- -
- Canonical SPDI
- NC_000003.12:136262023:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00004
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PCCB | - | - |
GRCh38 GRCh37 |
1174 | 1199 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Feb 26, 2024 | RCV000012795.35 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001136606.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Pathogenic
(Jan 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074157.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant summary: PCCB c.502G>A (p.Glu168Lys) results in a conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein … (more)
Variant summary: PCCB c.502G>A (p.Glu168Lys) results in a conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of 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 6e-06 in 166868 control chromosomes. c.502G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Propionic Acidemia (example, Rodriguez-Pombo_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Perez-Cedra_2003). The most pronounced variant effect results in undetectable levels (approximately 1%) of normal propionyl-CoA carboxylase (PCC) enzyme activity in vitro. Three 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. (less)
|
|
|
Likely pathogenic
(Aug 22, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000793689.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
|
Pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811590.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Nov 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001591310.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 168 of the PCCB protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 168 of the PCCB protein (p.Glu168Lys). 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: 9683601, 20549364). ClinVar contains an entry for this variant (Variation ID: 12015). 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: 11749052, 12757933). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004205188.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Mar 04, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002081475.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Pathogenic
(Aug 01, 1998)
|
no assertion criteria provided
Method: literature only
|
PROPIONIC ACIDEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033035.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 14.3% of the mutant alleles of Spanish patients with propionic acidemia (606054) and in 25% of the mutant alleles of Latin American patients, Rodriguez-Pombo … (more)
In 14.3% of the mutant alleles of Spanish patients with propionic acidemia (606054) and in 25% of the mutant alleles of Latin American patients, Rodriguez-Pombo et al. (1998) found a G-to-A transition at nucleotide 502 of the PCCB gene, resulting in a glu168-to-lys amino acid substitution. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Propionic acidemia
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000055690.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 168 of the PCCB protein (p.Glu168Lys). 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: 9683601, 20549364). ClinVar contains an entry for this variant (Variation ID: 12015). 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: 11749052, 12757933). For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: PCCB c.502G>A (p.Glu168Lys) results in a conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of 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 6e-06 in 166868 control chromosomes. c.502G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Propionic Acidemia (example, Rodriguez-Pombo_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Perez-Cedra_2003). The most pronounced variant effect results in undetectable levels (approximately 1%) of normal propionyl-CoA carboxylase (PCC) enzyme activity in vitro. Three 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.
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 168 of the PCCB protein (p.Glu168Lys). 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: 9683601, 20549364). ClinVar contains an entry for this variant (Variation ID: 12015). 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: 11749052, 12757933). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Propionic Acidemia. | Adam MP | - | 2024 | PMID: 22593918 |
| The molecular landscape of propionic acidemia and methylmalonic aciduria in Latin America. | Pérez B | Journal of inherited metabolic disease | 2010 | PMID: 20549364 |
| Functional analysis of PCCB mutations causing propionic acidemia based on expression studies in deficient human skin fibroblasts. | Pérez-Cerdá C | Biochimica et biophysica acta | 2003 | PMID: 12757933 |
| Propionic acidemia: analysis of mutant propionyl-CoA carboxylase enzymes expressed in Escherichia coli. | Chloupkova M | Human mutation | 2002 | PMID: 12007220 |
| Effect of PCCB gene mutations on the heteromeric and homomeric assembly of propionyl-CoA carboxylase. | Muro S | Molecular genetics and metabolism | 2001 | PMID: 11749052 |
| Human propionyl-CoA carboxylase beta subunit gene: exon-intron definition and mutation spectrum in Spanish and Latin American propionic acidemia patients. | Rodríguez-Pombo P | American journal of human genetics | 1998 | PMID: 9683601 |
Text-mined citations for rs121964960 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.