VCV000554669.10 - ClinVar

NM_000282.4(PCCA):c.183+4_183+7del

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(2)

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.183+4_183+7del

Variation ID: 554669 Accession: VCV000554669.10

Type and length

Microsatellite, 4 bp

Location

Cytogenetic: 13q32.3 13: 100102959-100102962 (GRCh38) [ NCBI UCSC ] 13: 100755213-100755216 (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	Feb 7, 2023	Feb 17, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000282.4:c.183+4_183+7del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_000282.3:c.183+4_183+7delAGTA
NM_001127692.3:c.106-8877_106-8874del		intron variant
NM_001178004.2:c.183+4_183+7del		splice donor
NM_001352605.2:c.183+4_183+7del		splice donor
NM_001352606.2:c.183+4_183+7del		splice donor
NM_001352607.2:c.106-8877_106-8874del		intron variant
NM_001352608.2:c.106-8877_106-8874del		intron variant
NM_001352609.2:c.183+4_183+7del		splice donor
NM_001352610.2:c.-684+4_-684+7del		splice donor
NM_001352611.2:c.-684+4_-684+7del		splice donor
NM_001352612.2:c.-684+4_-684+7del		splice donor
NC_000013.11:g.100102960AGTA[1]
NC_000013.10:g.100755214AGTA[1]
NG_008768.1:g.18878AGTA[1]

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000013.11:100102958:AAGTAAGTA:AAGTA

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.

Links

dbSNP: rs1555342581 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	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Feb 17, 2021	RCV000670345.9

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 31, 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: SCV000795186.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018
Pathogenic (Feb 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research, in vitro	Propionic acidemia Affected status: not applicable, yes Allele origin: germline, not applicable	Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics Accession: SCV001481999.1 First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021	Comment: PS3, PM2, PM3, PP3, PP4 Observation 1: Observation 2: Method: minigene splicing assay Result: exon skipping, corresponding to r.106_183del (p.His36_Lys61del)
Uncertain significance (Jun 26, 2019)	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: SCV001414278.2 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 17576681‚ 9536098 Comment: This sequence change falls in intron 2 of the PCCA gene. It does not directly change the encoded amino acid sequence of the PCCA protein, … (more) This sequence change falls in intron 2 of the PCCA gene. It does not directly change the encoded amino acid sequence of the PCCA protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PCCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 554669). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. (less)
Uncertain significance (Feb 28, 2020)	no assertion criteria provided Method: clinical testing	Propionic acidemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002094956.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This sequence change falls in intron 2 of the PCCA gene. It does not directly change the encoded amino acid sequence of the PCCA protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PCCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 554669). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs1555342581 ...

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.183+4_183+7del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1555342581 ...