ClinVar Genomic variation as it relates to human health
NM_000282.4(PCCA):c.1118T>A (p.Met373Lys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000282.4(PCCA):c.1118T>A (p.Met373Lys)
Variation ID: 12024 Accession: VCV000012024.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q32.3 13: 100301512 (GRCh38) [ NCBI UCSC ] 13: 100953766 (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 Oct 23, 2017 Feb 14, 2024 May 11, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000282.4:c.1118T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000273.2:p.Met373Lys missense NM_001127692.3:c.1040T>A NP_001121164.1:p.Met347Lys missense NM_001178004.2:c.1118T>A NP_001171475.1:p.Met373Lys missense NM_001352605.2:c.1118T>A NP_001339534.1:p.Met373Lys missense NM_001352606.2:c.1066-1412T>A intron variant NM_001352607.2:c.1040T>A NP_001339536.1:p.Met347Lys missense NM_001352608.2:c.988-1412T>A intron variant NM_001352609.2:c.1118T>A NP_001339538.1:p.Met373Lys missense NM_001352610.2:c.173T>A NP_001339539.1:p.Met58Lys missense NM_001352611.2:c.173T>A NP_001339540.1:p.Met58Lys missense NM_001352612.2:c.121-1412T>A intron variant NR_148027.2:n.1146T>A non-coding transcript variant NR_148028.2:n.1146T>A non-coding transcript variant NR_148029.2:n.1068T>A non-coding transcript variant NR_148030.2:n.1146T>A non-coding transcript variant NR_148031.2:n.1146T>A non-coding transcript variant NC_000013.11:g.100301512T>A NC_000013.10:g.100953766T>A NG_008768.1:g.217430T>A P05165:p.Met373Lys - Protein change
- M347K, M373K, M58K
- Other names
-
M348K
- Canonical SPDI
- NC_000013.11:100301511:T: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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- 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. |
|||
| PCCA | - | - |
GRCh38 GRCh37 |
1370 | 1491 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
May 11, 2023 | RCV000012804.35 |
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: SCV001139372.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Likely pathogenic
(Apr 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202891.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(May 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Propionic acidemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001580696.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PCCA function (PMID: 10101253). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PCCA function (PMID: 10101253). 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 PCCA protein function. ClinVar contains an entry for this variant (Variation ID: 12024). This variant is also known as M348K. This missense change has been observed in individual(s) with propionic acidemia (PMID: 10101253, 22033733, 33028371). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121964958, gnomAD 0.0009%). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 373 of the PCCA protein (p.Met373Lys). (less)
|
|
|
Pathogenic
(Mar 30, 1999)
|
no assertion criteria provided
Method: literature only
|
PROPIONIC ACIDEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033044.3
First in ClinVar: Apr 04, 2013 Last updated: May 04, 2020 |
Comment on evidence:
Richard et al. (1999) found that 2 of 24 PCCA mutant alleles from 12 unrelated patients with propionic acidemia (606054) carried a met348-to-lys mutation resulting … (more)
Richard et al. (1999) found that 2 of 24 PCCA mutant alleles from 12 unrelated patients with propionic acidemia (606054) carried a met348-to-lys mutation resulting from a 1043T-A transversion. To examine the effect of the mutation, which involved a highly conserved residue, they carried out in vitro expression of normal and mutant PCCA cDNA. They found that both wildtype and mutant proteins were imported into mitochondria and processed into the mature form with similar efficiency, but the mature mutant M348K protein decayed more rapidly than did the wildtype, indicating a reduced stability, which was probably the disease-causing mechanism. (less)
|
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. |
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Biochemical and genetic approaches to the prenatal diagnosis of propionic acidemia in 78 pregnancies. | Dai M | Orphanet journal of rare diseases | 2020 | PMID: 33028371 |
| Mutation analysis in 54 propionic acidemia patients. | Kraus JP | Journal of inherited metabolic disease | 2012 | PMID: 22033733 |
| Genetic heterogeneity in propionic acidemia patients with alpha-subunit defects. Identification of five novel mutations, one of them causing instability of the protein. | Richard E | Biochimica et biophysica acta | 1999 | PMID: 10101253 |
Text-mined citations for rs121964958 ...
HelpRecord 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.