VCV000554477.14 - ClinVar

NM_000282.4(PCCA):c.1593_1595del (p.Leu532del)

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.

(5)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(3); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000282.4(PCCA):c.1593_1595del (p.Leu532del)

Variation ID: 554477 Accession: VCV000554477.14

Type and length

Deletion, 3 bp

Location

Cytogenetic: 13q32.3 13: 100340209-100340211 (GRCh38) [ NCBI UCSC ] 13: 100992463-100992465 (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 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000282.4:c.1593_1595del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000273.2:p.Leu532del	inframe deletion
NM_001127692.3:c.1515_1517del	NP_001121164.1:p.Leu506del	inframe deletion
NM_001178004.2:c.1593_1595del	NP_001171475.1:p.Leu532del	inframe deletion
NM_001352605.2:c.1593_1595del	NP_001339534.1:p.Leu532del	inframe deletion
NM_001352606.2:c.1449_1451del	NP_001339535.1:p.Leu484del	inframe deletion
NM_001352607.2:c.1515_1517del	NP_001339536.1:p.Leu506del	inframe deletion
NM_001352608.2:c.1371_1373del	NP_001339537.1:p.Leu458del	inframe deletion
NM_001352609.2:c.1593_1595del	NP_001339538.1:p.Leu532del	inframe deletion
NM_001352610.2:c.648_650del	NP_001339539.1:p.Leu217del	inframe deletion
NM_001352611.2:c.648_650del	NP_001339540.1:p.Leu217del	inframe deletion
NM_001352612.2:c.504_506del	NP_001339541.1:p.Leu169del	inframe deletion
NR_148027.2:n.1705_1707del		non-coding transcript variant
NR_148028.2:n.1705_1707del		non-coding transcript variant
NR_148029.2:n.1627_1629del		non-coding transcript variant
NR_148030.2:n.1705_1707del		non-coding transcript variant
NR_148031.2:n.1621_1623del		non-coding transcript variant
NC_000013.11:g.100340209_100340211del
NC_000013.10:g.100992463_100992465del
NG_008768.1:g.256127_256129del

... more HGVS ... less HGVS

Protein change

L532del, L169del, L458del, L484del, L217del, L506del

Other names

Canonical SPDI

NC_000013.11:100340208:ATT:

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) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs937519016 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	1371	1492

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	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Feb 13, 2024	RCV000670118.10
not provided	Likely pathogenic (1)	criteria provided, single submitter	Aug 16, 2019	RCV001565479.3

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.
Uncertain significance (Oct 19, 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: SCV000794934.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 12559849
Likely pathogenic (Aug 16, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001788833.1 First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021	Comment: Reported in an individual reported to have propionic acidemia who also had a second variant identified in the PCCA gene; although, no information was provided … (more) Reported in an individual reported to have propionic acidemia who also had a second variant identified in the PCCA gene; although, no information was provided about how the diagnosis of propionic acidemia was established (Perez et al., 2003); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12559849, 15464417) (less)
Likely pathogenic (Jan 21, 2024)	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: SCV002302089.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 12559849 Comment: This variant, c.1593_1595del, results in the deletion of 1 amino acid(s) of the PCCA protein (p.Leu532del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.1593_1595del, results in the deletion of 1 amino acid(s) of the PCCA protein (p.Leu532del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individual(s) with propionic acidemia (PMID: 12559849; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554477). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Likely pathogenic (Feb 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Propionic acidemia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202848.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (Jun 18, 2020)	no assertion criteria provided Method: clinical testing	Propionic acidemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002094979.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

Reported in an individual reported to have propionic acidemia who also had a second variant identified in the PCCA gene; although, no information was provided about how the diagnosis of propionic acidemia was established (Perez et al., 2003); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12559849, 15464417)

Comment:

This variant, c.1593_1595del, results in the deletion of 1 amino acid(s) of the PCCA protein (p.Leu532del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individual(s) with propionic acidemia (PMID: 12559849; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554477). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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
Propionic acidemia: identification of twenty-four novel mutations in Europe and North America.	Pérez B	Molecular genetics and metabolism	2003	PMID: 12559849

Text-mined citations for rs937519016 ...

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.1593_1595del (p.Leu532del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs937519016 ...