VCV001333250.5 - ClinVar

NM_006218.4(PIK3CA):c.1345C>A (p.Pro449Thr)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

2 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006218.4(PIK3CA):c.1345C>A (p.Pro449Thr)

Variation ID: 1333250 Accession: VCV001333250.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q26.32 3: 179210279 (GRCh38) [ NCBI UCSC ] 3: 178928067 (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	Jan 15, 2022	Feb 11, 2022	Jan 3, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_006218.4:c.1345C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006209.2:p.Pro449Thr	missense
NC_000003.12:g.179210279C>A
NC_000003.11:g.178928067C>A
NG_012113.2:g.66757C>A
LRG_310:g.66757C>A

... more HGVS ... less HGVS

Protein change

P449T

Other names

Canonical SPDI

NC_000003.12:179210278:C:A

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

ClinGen: CA355261904 dbSNP: rs1724674149 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.
PIK3CA		No evidence available	No evidence available	GRCh38 GRCh37	1576	1614

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.
Megalencephaly-capillary malformation-polymicrogyria syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 3, 2022	RCV001807938.7

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.	Expand all rows Collapse all rows 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 (Jan 03, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Megalencephaly-capillary malformation-polymicrogyria syndrome	3billion Accession: SCV002058239.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:27631024 PMID:27631024 Comment: show The variant has been previously reported as de novo in a similarly affected individual (PMID: 27631024, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PIK3CA related disorder (PMID:27631024, PS1_P). A different missense change at the same codon (p.Pro449Ser) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000864863, PM5_M). A missense variant is a common mechanism associated with Megalencephaly-capillary malformation-polymicrogyria syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Capillary malformation (present) , Hemihypertrophy (present) , Macrocephaly (present) Zygosity: Single Heterozygote Platform type: whole exome sequencing Platform name: NovaSeq

Likely pathogenic (Jul 15, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Megalencephaly-capillary malformation-polymicrogyria syndrome	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002061495.2 First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022	Comment: show PM6, PM1, PM2, PP2, PP3, PS4_Moderate (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

The variant has been previously reported as de novo in a similarly affected individual (PMID: 27631024, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PIK3CA related disorder (PMID:27631024, PS1_P). A different missense change at the same codon (p.Pro449Ser) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000864863, PM5_M). A missense variant is a common mechanism associated with Megalencephaly-capillary malformation-polymicrogyria syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.	Mirzaa G	JCI insight	2016	PMID: 27631024

Text-mined citations for rs1724674149 ...

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 May 17, 2025