VCV000554310.11 - ClinVar

NM_000282.4(PCCA):c.1268C>T (p.Pro423Leu)

Germline

Classification

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.

(4)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000282.4(PCCA):c.1268C>T (p.Pro423Leu)

Variation ID: 554310 Accession: VCV000554310.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q32.3 13: 100302982 (GRCh38) [ NCBI UCSC ] 13: 100955236 (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	Aug 5, 2018	Jun 17, 2024	Feb 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000282.4:c.1268C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000273.2:p.Pro423Leu	missense
NM_001127692.3:c.1190C>T	NP_001121164.1:p.Pro397Leu	missense
NM_001178004.2:c.1268C>T	NP_001171475.1:p.Pro423Leu	missense
NM_001352605.2:c.1268C>T	NP_001339534.1:p.Pro423Leu	missense
NM_001352606.2:c.1124C>T	NP_001339535.1:p.Pro375Leu	missense
NM_001352607.2:c.1190C>T	NP_001339536.1:p.Pro397Leu	missense
NM_001352608.2:c.1046C>T	NP_001339537.1:p.Pro349Leu	missense
NM_001352609.2:c.1268C>T	NP_001339538.1:p.Pro423Leu	missense
NM_001352610.2:c.323C>T	NP_001339539.1:p.Pro108Leu	missense
NM_001352611.2:c.323C>T	NP_001339540.1:p.Pro108Leu	missense
NM_001352612.2:c.179C>T	NP_001339541.1:p.Pro60Leu	missense
NR_148027.2:n.1296C>T		non-coding transcript variant
NR_148028.2:n.1296C>T		non-coding transcript variant
NR_148029.2:n.1218C>T		non-coding transcript variant
NR_148030.2:n.1296C>T		non-coding transcript variant
NR_148031.2:n.1296C>T		non-coding transcript variant
NC_000013.11:g.100302982C>T
NC_000013.10:g.100955236C>T
NG_008768.1:g.218900C>T

... more HGVS ... less HGVS

Protein change

P423L, P397L, P60L, P375L, P108L, P349L

Other names

Canonical SPDI

NC_000013.11:100302981:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs1443858896 VarSome

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
Gene	OMIM	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.
Propionic acidemia	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 7, 2024	RCV000669921.13

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.
Likely pathogenic (Oct 16, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Propionic acidemia Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000794721.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (3) PubMed: 15059621‚ 20549364‚ 22033733
Likely pathogenic (May 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Propionic acidemia Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003813205.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Nov 07, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Propionic acidemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001222394.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 10518292‚ 20549364‚ 22033733‚ 2037281 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 423 of the PCCA protein (p.Pro423Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 423 of the PCCA protein (p.Pro423Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with propionic acidemia (PMID: 10518292, 20549364, 22033733). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 1193C>T; P398L. ClinVar contains an entry for this variant (Variation ID: 554310). 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 PCCA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PCCA function (PMID: 2037281, 22033733). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 07, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Propionic acidemia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005055082.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 423 of the PCCA protein (p.Pro423Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with propionic acidemia (PMID: 10518292, 20549364, 22033733). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 1193C>T; P398L. ClinVar contains an entry for this variant (Variation ID: 554310). 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 PCCA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PCCA function (PMID: 2037281, 22033733). 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation analysis in 54 propionic acidemia patients.	Kraus JP	Journal of inherited metabolic disease	2012	PMID: 22033733
The molecular landscape of propionic acidemia and methylmalonic aciduria in Latin America.	Pérez B	Journal of inherited metabolic disease	2010	PMID: 20549364
Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia.	Yang X	Molecular genetics and metabolism	2004	PMID: 15059621
Mutation analysis of the propionyl-CoA carboxylase alpha-subunit gene in four Japanese patients with propionic acidaemia.	Ohura T	Journal of inherited metabolic disease	1999	PMID: 10518292
Genetic heterogeneity of propionic acidemia: analysis of 15 Japanese patients.	Ohura T	Human genetics	1991	PMID: 2037281

Text-mined citations for rs1443858896 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000282.4(PCCA):c.1268C>T (p.Pro423Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1443858896 ...