This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 335 of the PTEN protein (p.Arg335Gln). 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: 28526761). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 427580). 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 not expected to disrupt PTEN protein function with a negative predictive value of 80%. This variant disrupts the p.Arg335 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 10920277), which suggests that this may be a clinically significant amino acid residue. 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.
ClinVar Genomic variation as it relates to human health
NM_000314.8(PTEN):c.1004G>A (p.Arg335Gln)
Germline
Classification
Help
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.
(6)
Help
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); Likely pathogenic(1); Uncertain significance(3)
Pathogenic(1); Likely pathogenic(1); Uncertain significance(3)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000314.8(PTEN):c.1004G>A (p.Arg335Gln)
Variation ID: 427580 Accession: VCV000427580.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 87961096 (GRCh38) [ NCBI UCSC ] 10: 89720853 (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 Jun 3, 2017 Oct 26, 2024 Nov 24, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000314.8:c.1004G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000305.3:p.Arg335Gln missense NM_001304717.5:c.1523G>A NP_001291646.4:p.Arg508Gln missense NM_001304718.2:c.413G>A NP_001291647.1:p.Arg138Gln missense NC_000010.11:g.87961096G>A NC_000010.10:g.89720853G>A NG_007466.2:g.102658G>A LRG_311:g.102658G>A LRG_311t1:c.1004G>A - Protein change
- R335Q, R508Q, R138Q
- Other names
- -
- Canonical SPDI
- NC_000010.11:87961095:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| PTEN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
3102 | 3612 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Nov 24, 2023 | RCV000490592.8 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV001799513.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 21, 2023 | RCV002404284.3 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jun 1, 2022 | RCV004767301.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
PTEN Hamartoma Tumor Syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
|
Herman Laboratory, Nationwide Children's Hospital
Accession: SCV000579259.1
First in ClinVar: Jun 03, 2017 Last updated: Jun 03, 2017 |
Observation 1:
Clinical Features:
Global developmental delay (present) , Speech Apraxia (present) , Seizures (present) , Hemangioma (present)
Family history: yes
Sex: male
Ethnicity/Population group: Caucasian
Tissue: Blood
Comment on evidence:
Normocephalic with MRI revealing bilateral asymmetric areas of tissue injury and volume loss in periventricular white matter of the frontal lobes. EEG is abnormal with … (more)
Normocephalic with MRI revealing bilateral asymmetric areas of tissue injury and volume loss in periventricular white matter of the frontal lobes. EEG is abnormal with multifocal epileptiform sharp waves in the left frontal region and right temporal region. (less)
Observation 2:
Clinical Features:
Macrocephaly (present) , Autism specturm disorder (present) , Developmental delay (present) , Hemangioma (present)
Family history: yes
Sex: female
Ethnicity/Population group: Caucasian
Tissue: Blood
Comment on evidence:
Patient identified after PTEN mutation identified in sibling. Macrocephaly (+2.6 SD)
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Macrocephaly-autism syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV002043787.2
First in ClinVar: Dec 29, 2021 Last updated: Mar 05, 2022 |
Sex: male
Tissue: Blood
Secondary finding: no
|
|
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Uncertain significance
(Nov 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PTEN hamartoma tumor syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002225547.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 335 of the PTEN protein (p.Arg335Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 335 of the PTEN protein (p.Arg335Gln). 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: 28526761). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 427580). 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 not expected to disrupt PTEN protein function with a negative predictive value of 80%. This variant disrupts the p.Arg335 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 10920277), which suggests that this may be a clinically significant amino acid residue. 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)
|
|
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Uncertain Significance
(Nov 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PTEN hamartoma tumor syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004835546.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces arginine with glutamine at codon 335 of the PTEN protein. A functional assay using an artificial humanized yeast model yielded inconclusive … (more)
This missense variant replaces arginine with glutamine at codon 335 of the PTEN protein. A functional assay using an artificial humanized yeast model yielded inconclusive results for this variant's impact on lipid phosphatase activity (PMID: 29706350). This variant has been reported in two families with individuals that were affected with clinical features of PTEN-related disorders, with one individual having a diagnosis of Bannayan-Riley-Ruvalcaba syndrome (PMID: 28526761, 36681873). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Mar 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002713677.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R335Q variant (also known as c.1004G>A), located in coding exon 8 of the PTEN gene, results from a G to A substitution at nucleotide … (more)
The p.R335Q variant (also known as c.1004G>A), located in coding exon 8 of the PTEN gene, results from a G to A substitution at nucleotide position 1004. The arginine at codon 335 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported to segregate with disease in one family in a 5 year-old and with global developmental delays, EEG abnormalities and seizures, in his sibling affected with developmental delay, macrocephaly and hemangiomas and their father affected with penile freckling, learning difficulties, and macrocephaly (Hansen-Kiss E et al. J. Med. Genet., 2017 07;54:471-478). In a humanized yeast model, lipid phosphatase activity for this variant is similar to wildtype (Mighell TL et al. Am. J. Hum. Genet., 2018 05;102:943-955). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
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Likely pathogenic
(Jun 01, 2022)
|
no assertion criteria provided
Method: provider interpretation
|
Familial meningioma
Affected status: yes
Allele origin:
inherited
|
Solve-RD Consortium
Accession: SCV005091343.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
|
Comment:
Variant confirmed as disease-causing by referring clinical team
|
Comment:
Comment:
This missense variant replaces arginine with glutamine at codon 335 of the PTEN protein. A functional assay using an artificial humanized yeast model yielded inconclusive results for this variant's impact on lipid phosphatase activity (PMID: 29706350). This variant has been reported in two families with individuals that were affected with clinical features of PTEN-related disorders, with one individual having a diagnosis of Bannayan-Riley-Ruvalcaba syndrome (PMID: 28526761, 36681873). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.R335Q variant (also known as c.1004G>A), located in coding exon 8 of the PTEN gene, results from a G to A substitution at nucleotide position 1004. The arginine at codon 335 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported to segregate with disease in one family in a 5 year-old and with global developmental delays, EEG abnormalities and seizures, in his sibling affected with developmental delay, macrocephaly and hemangiomas and their father affected with penile freckling, learning difficulties, and macrocephaly (Hansen-Kiss E et al. J. Med. Genet., 2017 07;54:471-478). In a humanized yeast model, lipid phosphatase activity for this variant is similar to wildtype (Mighell TL et al. Am. J. Hum. Genet., 2018 05;102:943-955). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Variant confirmed as disease-causing by referring clinical team
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:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 335 of the PTEN protein (p.Arg335Gln). 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: 28526761). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 427580). 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 not expected to disrupt PTEN protein function with a negative predictive value of 80%. This variant disrupts the p.Arg335 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 10920277), which suggests that this may be a clinically significant amino acid residue. 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.
Comment:
This missense variant replaces arginine with glutamine at codon 335 of the PTEN protein. A functional assay using an artificial humanized yeast model yielded inconclusive results for this variant's impact on lipid phosphatase activity (PMID: 29706350). This variant has been reported in two families with individuals that were affected with clinical features of PTEN-related disorders, with one individual having a diagnosis of Bannayan-Riley-Ruvalcaba syndrome (PMID: 28526761, 36681873). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.R335Q variant (also known as c.1004G>A), located in coding exon 8 of the PTEN gene, results from a G to A substitution at nucleotide position 1004. The arginine at codon 335 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported to segregate with disease in one family in a 5 year-old and with global developmental delays, EEG abnormalities and seizures, in his sibling affected with developmental delay, macrocephaly and hemangiomas and their father affected with penile freckling, learning difficulties, and macrocephaly (Hansen-Kiss E et al. J. Med. Genet., 2017 07;54:471-478). In a humanized yeast model, lipid phosphatase activity for this variant is similar to wildtype (Mighell TL et al. Am. J. Hum. Genet., 2018 05;102:943-955). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing. | Denommé-Pichon AS | Genetics in medicine : official journal of the American College of Medical Genetics | 2023 | PMID: 36681873 |
| A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships. | Mighell TL | American journal of human genetics | 2018 | PMID: 29706350 |
| A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children. | Hansen-Kiss E | Journal of medical genetics | 2017 | PMID: 28526761 |
| Mutation analysis of the PTEN / MMAC1 gene in Japanese patients with Cowden disease. | Sawada T | Japanese journal of cancer research : Gann | 2000 | PMID: 10920277 |
Text-mined citations for rs1085308040 ...
HelpThese 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 Oct 27, 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.