ClinVar Genomic variation as it relates to human health
NM_000314.8(PTEN):c.755A>T (p.Asp252Val)
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
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NM_000314.8(PTEN):c.755A>T (p.Asp252Val)
Variation ID: 575811 Accession: VCV000575811.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 87957973 (GRCh38) [ NCBI UCSC ] 10: 89717730 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 10, 2018 May 1, 2024 Dec 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000314.8:c.755A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000305.3:p.Asp252Val missense NM_001304717.5:c.1274A>T NP_001291646.4:p.Asp425Val missense NM_001304718.2:c.164A>T NP_001291647.1:p.Asp55Val missense NC_000010.11:g.87957973A>T NC_000010.10:g.89717730A>T NG_007466.2:g.99535A>T LRG_311:g.99535A>T LRG_311t1:c.755A>T - Protein change
- D252V, D55V, D425V
- Other names
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- Canonical SPDI
- NC_000010.11:87957972:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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PTEN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
3084 | 3584 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Dec 7, 2023 | RCV000698131.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 4, 2016 | RCV002388286.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 13, 2023 | RCV003479201.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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. |
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Likely pathogenic
(Nov 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cowden syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223706.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: PTEN c.755A>T (p.Asp252Val) results in a non-conservative amino acid change in the encoded protein sequence. A different variant at the same codon, c.755A>G … (more)
Variant summary: PTEN c.755A>T (p.Asp252Val) results in a non-conservative amino acid change in the encoded protein sequence. A different variant at the same codon, c.755A>G (p.Asp252Gly) has been classified as Likely pathogenic/pathogenic supporting the critical relevance of the Aspartate 252 residue to PTEN protein function. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251422 control chromosomes. c.755A>T has been reported in the literature in individuals affected with autism spectrum disorders, PTEN-hamartoma syndrome, Cowden syndrome and in settings of Thyroid nodules (example, Frazier_2015, Kim_2022, Yehia_2022, Nizialek_2015, Quaytman_2022). These data indicate that the variant may be associated with disease. Several studies have reported an impact on PTEN-function, however, these were not weighted in the context of this evaluation. The following publications have been ascertained in the context of this evaluation (PMID: 25288137, 34492006, 36175890, 29785012, 29706350, 25669429, 31232187, 35723418, 31427284, 25527629, 35241692). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Dec 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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PTEN hamartoma tumor syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000826774.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 252 of the PTEN protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 252 of the PTEN protein (p.Asp252Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 25288137, 25669429; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 575811). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 27514801, 29706350, 29785012). This variant disrupts the p.Asp252 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23335809, 25527629, 26579216, 29373119). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002670873.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D252V variant (also known as c.755A>T), located in coding exon 7 of the PTEN gene, results from an A to T substitution at nucleotide … (more)
The p.D252V variant (also known as c.755A>T), located in coding exon 7 of the PTEN gene, results from an A to T substitution at nucleotide position 755. The aspartic acid at codon 252 is replaced by valine, an amino acid with highly dissimilar properties. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lee JO, et al. Cell 1999 Oct; 99(3):323-34). This alteration was described in a cohort of individuals with autism spectrum disorder (Frazier TW, et al. Mol. Psychiatry 2015 Sep; 20(9):1132-8). Additionally, another amino acid change at the same codon (p.D252G) has been identified in a child with an autism spectrum disorder and macrocephaly as well as in a series suspected-PHTS patients (Spinelli L, et al. J. Med. Genet. 2015 Feb; 52(2):128-34. Pilarski R et al, J. Med. Genet. 2011 Aug; 48(8):505-12. Butler MG et al, J. Med. Genet. 2005 Apr; 42(4):318-21). The p.D252V variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0005% (greater than 200000 alleles tested) in our clinical cohort. This variant was detected in an individual meeting diagnostic criteria for Cowden syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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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
HelpTitle | Author | Journal | Year | Link |
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Clinical and genetic analyses of patients with lateralized overgrowth. | Kim YM | BMC medical genomics | 2022 | PMID: 36175890 |
Clinicopathologic features of thyroid nodules with PTEN mutations on preoperative testing. | Quaytman JA | Endocrine-related cancer | 2022 | PMID: 35723418 |
Distinct metabolic profiles associated with autism spectrum disorder versus cancer in individuals with germline PTEN mutations. | Yehia L | NPJ genomic medicine | 2022 | PMID: 35241692 |
A scalable Drosophila assay for clinical interpretation of human PTEN variants in suppression of PI3K/AKT induced cellular proliferation. | Ganguly P | PLoS genetics | 2021 | PMID: 34492006 |
Analyzing aggregation propensities of clinically relevant PTEN mutants: a new culprit in pathogenesis of cancer and other PTENopathies. | Palumbo E | Journal of biomolecular structure & dynamics | 2020 | PMID: 31232187 |
PTEN in Autism and Neurodevelopmental Disorders. | Rademacher S | Cold Spring Harbor perspectives in medicine | 2019 | PMID: 31427284 |
Multiplex assessment of protein variant abundance by massively parallel sequencing. | Matreyek KA | Nature genetics | 2018 | PMID: 29785012 |
A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships. | Mighell TL | American journal of human genetics | 2018 | PMID: 29706350 |
Nuclear Excluded Autism-Associated Phosphatase and Tensin Homolog Mutations Dysregulate Neuronal Growth. | Fricano-Kugler CJ | Biological psychiatry | 2018 | PMID: 29373119 |
Tailor-Made Protein Tyrosine Phosphatases: In Vitro Site-Directed Mutagenesis of PTEN and PTPRZ-B. | Luna S | Methods in molecular biology (Clifton, N.J.) | 2016 | PMID: 27514801 |
Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits. | He X | Molecular autism | 2015 | PMID: 26579216 |
KLLN epigenotype-phenotype associations in Cowden syndrome. | Nizialek EA | European journal of human genetics : EJHG | 2015 | PMID: 25669429 |
Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes. | Spinelli L | Journal of medical genetics | 2015 | PMID: 25527629 |
Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism. | Frazier TW | Molecular psychiatry | 2015 | PMID: 25288137 |
High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. | Bubien V | Journal of medical genetics | 2013 | PMID: 23335809 |
Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. | Pilarski R | Journal of medical genetics | 2011 | PMID: 21659347 |
Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. | Butler MG | Journal of medical genetics | 2005 | PMID: 15805158 |
Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. | Lee JO | Cell | 1999 | PMID: 10555148 |
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Text-mined citations for rs121909239 ...
HelpRecord last updated May 01, 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.