The p.Arg173His variant has been reported in 4 individuals with clinical feature s of Cowden syndrome (Lachlan 2007, Mcbride 2010, Bubien 2013) and segregated wi th disease in 2 affected relatives from 2 different families (Lachlan 2007, Varg a 2004). In addition, it segregated with macrocephaly in 1 relative from a third family (McBride 2010). This variant has been identified in 1/10324 African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs121913294). This variant has been observed as a somatic mutation in t umors, including glioblastoma (Duerr 1998) and colorectal cancer (Day 2013). The p.Arg173His variant is associated with decreased protein activity in vitro (Han 2000, Rodriguez-Escudero 2011). However, these types of assays may not accurate ly represent biological function. In summary, although additional studies are re quired to fully establish its clinical significance, the p.Arg173His variant is likely pathogenic in an autosomal dominant manner.
ClinVar Genomic variation as it relates to human health
NM_000314.8(PTEN):c.518G>A (p.Arg173His)
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.
(14)
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.
Pathogenic/Likely pathogenic
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity 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.
Oncogenic
1
criteria provided, single submitter
Variant Details
- Identifiers
-
NM_000314.8(PTEN):c.518G>A (p.Arg173His)
Variation ID: 376032 Accession: VCV000376032.53
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q23.31 10: 87952143 (GRCh38) [ NCBI UCSC ] 10: 89711900 (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 Mar 8, 2017 Oct 20, 2024 Dec 9, 2023 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000314.8:c.518G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000305.3:p.Arg173His missense NM_001304717.5:c.1037G>A NP_001291646.4:p.Arg346His missense NM_001304718.2:c.-74G>A 5 prime UTR NC_000010.11:g.87952143G>A NC_000010.10:g.89711900G>A NG_007466.2:g.93705G>A LRG_311:g.93705G>A LRG_311t1:c.518G>A - Protein change
- R173H, R346H
- Other names
- -
- Canonical SPDI
- NC_000010.11:87952142:G:A
-
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.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- 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 |
3098 | 3607 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000432256.2 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 12, 2022 | RCV000484180.33 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 9, 2023 | RCV000490595.17 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 27, 2023 | RCV002338980.4 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 28, 2023 | RCV002289517.6 |
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:
maternal,
paternal
|
Herman Laboratory, Nationwide Children's Hospital
Accession: SCV000579279.1
First in ClinVar: Jun 03, 2017 Last updated: Jun 03, 2017 |
Observation 1:
Clinical Features:
Macrocephaly (present) , Café au Lait (present) , Nevus (present) , Thyroid abnormalities (present) , Attention deficit disorder (present)
Family history: yes
Sex: female
Ethnicity/Population group: Caucasian
Tissue: Blood
Comment on evidence:
Patient identified after PTEN diagnosis in sibling. Enlarged hyperemic thyroid gland and high TSH levels. Macrocephaly (+4 SD)
Observation 2:
Clinical Features:
Macrocephaly (present) , Developmental delay (present)
Family history: yes
Sex: male
Ethnicity/Population group: Caucasian
Tissue: Blood
Comment on evidence:
Macrocephaly (+5 SD)
Observation 3:
Clinical Features:
Macrocephaly (present) , Autism spectrum disorder (present) , Global developmental delay (present) , Undescended right testes (present)
Family history: yes
Sex: male
Ethnicity/Population group: Caucasian
Tissue: Blood
Comment on evidence:
Macrocephaly (+3.7 SD)
|
|
|
Likely pathogenic
(Oct 20, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
PTEN hamartoma tumor syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711962.2
First in ClinVar: Apr 09, 2018 Last updated: Oct 10, 2018 |
Comment:
The p.Arg173His variant has been reported in 4 individuals with clinical feature s of Cowden syndrome (Lachlan 2007, Mcbride 2010, Bubien 2013) and segregated wi … (more)
The p.Arg173His variant has been reported in 4 individuals with clinical feature s of Cowden syndrome (Lachlan 2007, Mcbride 2010, Bubien 2013) and segregated wi th disease in 2 affected relatives from 2 different families (Lachlan 2007, Varg a 2004). In addition, it segregated with macrocephaly in 1 relative from a third family (McBride 2010). This variant has been identified in 1/10324 African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs121913294). This variant has been observed as a somatic mutation in t umors, including glioblastoma (Duerr 1998) and colorectal cancer (Day 2013). The p.Arg173His variant is associated with decreased protein activity in vitro (Han 2000, Rodriguez-Escudero 2011). However, these types of assays may not accurate ly represent biological function. In summary, although additional studies are re quired to fully establish its clinical significance, the p.Arg173His variant is likely pathogenic in an autosomal dominant manner. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cowden syndrome 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581229.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS1, PM1, PM5, PM2_SUP, PP2, PP3
|
Number of individuals with the variant: 2
Sex: male
|
|
|
Pathogenic
(Dec 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000566605.7
First in ClinVar: Apr 27, 2017 Last updated: Dec 17, 2022 |
Comment:
Published functional studies demonstrate a damaging effect: absent or reduced phosphatase activity (Han et al., 2000; Rodriguez-Escudero et al., 2011; Mighell et al., 2018); In … (more)
Published functional studies demonstrate a damaging effect: absent or reduced phosphatase activity (Han et al., 2000; Rodriguez-Escudero et al., 2011; Mighell et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21828076, 25527629, 23335809, 30720243, 29625052, 24721394, 20533527, 23161105, 28526761, 17526800, 21659347, 26800850, 28201779, 28304377, 28984400, 16506206, 11875759, 20718038, 18986487, 29706350, 19265751, 24475377, 33482836, 36192478, 10866302) (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Cowden syndrome 1
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820282.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
The missense variant p.R173H in PTEN (NM_000314.8) has been reported before both in a patient with developmental delay (Varga EA et al) as well as … (more)
The missense variant p.R173H in PTEN (NM_000314.8) has been reported before both in a patient with developmental delay (Varga EA et al) as well as in patients with PTEN related hamartoma syndrome (Bubien et al; Hansen et al).Functional studies revealed reduced phosphatse activity (Rodriguez-Escudero et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic. The p.R173H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 173 of PTEN is conserved in all mammalian species. The nucleotide c.518 in PTEN is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Hypotonia (present) , Intellectual disability (present) , Cardiomyopathy (present) , Autistic behavior (present) , Febrile seizure (within the age range … (more)
Global developmental delay (present) , Hypotonia (present) , Intellectual disability (present) , Cardiomyopathy (present) , Autistic behavior (present) , Febrile seizure (within the age range of 3 months to 6 years) (present) , Anxiety (present) (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
PTEN-related disorders
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046133.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a heterozygous change in patients with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 23335809, 20533527, 28526761). In vitro … (more)
This variant has been previously reported as a heterozygous change in patients with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 23335809, 20533527, 28526761). In vitro assays showed that this variant is associated with decreased phosphatase activity (PMID: 21828076, 10866302). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001 % (2/251148) and thus is presumed to be rare. The c.518G>A (p.Arg173His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.518G>A (p.Arg173His) variant is classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Sep 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cowden syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004188723.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302]. This variant has been reported in multiple individuals with … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17526800, 18626099, 19265751, 20533527, 23335809]. (less)
|
|
|
Pathogenic
(Dec 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PTEN hamartoma tumor syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000645595.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 173 of the PTEN protein (p.Arg173His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 173 of the PTEN protein (p.Arg173His). This variant is present in population databases (rs121913294, gnomAD 0.01%). This missense change has been observed in individuals with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 20533527, 23335809; Invitae). ClinVar contains an entry for this variant (Variation ID: 376032). 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 expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302). This variant disrupts the p.Arg173 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10866302, 17526800, 25669429, 28475857). 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)
|
|
|
Likely pathogenic
(Apr 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002643221.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R173H variant (also known as c.518G>A), located in coding exon 6 of the PTEN gene, results from a G to A substitution at nucleotide … (more)
The p.R173H variant (also known as c.518G>A), located in coding exon 6 of the PTEN gene, results from a G to A substitution at nucleotide position 518. The arginine at codon 173 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with clinical features of PTEN-hamartoma tumor syndrome (Hansen-Kiss E et al. J. Med. Genet., 2017 07;54:471-478; Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Varga EA et al. Genet. Med., 2009 Feb;11:111-7; McBride KL et al. Autism Res, 2010 Jun;3:137-41; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; van der Velden JJ. et al. Int. J. Dermatol. 2008 Nov;47 Suppl 1:45-8). In one study, functional assays demonstrated that this alteration inactivates phosphastase activity (Han SY et al. Cancer Res., 2000 Jun;60:3147-51); however, in vivo yeast assays demonstrated partial phosphastase activity in another study (Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). Another study determined that p.R173H has an intermediate effect on regulating p53 and Gata3 levels compared to wild-type and nonsense alleles (Xu J et al. Transl Oncol, 2014 Apr;7:196-205.e1). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334626.25
First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of brain
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504815.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000692014.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954946.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973342.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
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Comment:
Comment:
Published functional studies demonstrate a damaging effect: absent or reduced phosphatase activity (Han et al., 2000; Rodriguez-Escudero et al., 2011; Mighell et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21828076, 25527629, 23335809, 30720243, 29625052, 24721394, 20533527, 23161105, 28526761, 17526800, 21659347, 26800850, 28201779, 28304377, 28984400, 16506206, 11875759, 20718038, 18986487, 29706350, 19265751, 24475377, 33482836, 36192478, 10866302)
Comment:
The missense variant p.R173H in PTEN (NM_000314.8) has been reported before both in a patient with developmental delay (Varga EA et al) as well as in patients with PTEN related hamartoma syndrome (Bubien et al; Hansen et al).Functional studies revealed reduced phosphatse activity (Rodriguez-Escudero et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic. The p.R173H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 173 of PTEN is conserved in all mammalian species. The nucleotide c.518 in PTEN is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant has been previously reported as a heterozygous change in patients with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 23335809, 20533527, 28526761). In vitro assays showed that this variant is associated with decreased phosphatase activity (PMID: 21828076, 10866302). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001 % (2/251148) and thus is presumed to be rare. The c.518G>A (p.Arg173His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.518G>A (p.Arg173His) variant is classified as Pathogenic.
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17526800, 18626099, 19265751, 20533527, 23335809].
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 173 of the PTEN protein (p.Arg173His). This variant is present in population databases (rs121913294, gnomAD 0.01%). This missense change has been observed in individuals with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 20533527, 23335809; Invitae). ClinVar contains an entry for this variant (Variation ID: 376032). 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 expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302). This variant disrupts the p.Arg173 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10866302, 17526800, 25669429, 28475857). 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.
Comment:
The p.R173H variant (also known as c.518G>A), located in coding exon 6 of the PTEN gene, results from a G to A substitution at nucleotide position 518. The arginine at codon 173 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with clinical features of PTEN-hamartoma tumor syndrome (Hansen-Kiss E et al. J. Med. Genet., 2017 07;54:471-478; Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Varga EA et al. Genet. Med., 2009 Feb;11:111-7; McBride KL et al. Autism Res, 2010 Jun;3:137-41; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; van der Velden JJ. et al. Int. J. Dermatol. 2008 Nov;47 Suppl 1:45-8). In one study, functional assays demonstrated that this alteration inactivates phosphastase activity (Han SY et al. Cancer Res., 2000 Jun;60:3147-51); however, in vivo yeast assays demonstrated partial phosphastase activity in another study (Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). Another study determined that p.R173H has an intermediate effect on regulating p53 and Gata3 levels compared to wild-type and nonsense alleles (Xu J et al. Transl Oncol, 2014 Apr;7:196-205.e1). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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:
The p.Arg173His variant has been reported in 4 individuals with clinical feature s of Cowden syndrome (Lachlan 2007, Mcbride 2010, Bubien 2013) and segregated wi th disease in 2 affected relatives from 2 different families (Lachlan 2007, Varg a 2004). In addition, it segregated with macrocephaly in 1 relative from a third family (McBride 2010). This variant has been identified in 1/10324 African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs121913294). This variant has been observed as a somatic mutation in t umors, including glioblastoma (Duerr 1998) and colorectal cancer (Day 2013). The p.Arg173His variant is associated with decreased protein activity in vitro (Han 2000, Rodriguez-Escudero 2011). However, these types of assays may not accurate ly represent biological function. In summary, although additional studies are re quired to fully establish its clinical significance, the p.Arg173His variant is likely pathogenic in an autosomal dominant manner.
Comment:
Published functional studies demonstrate a damaging effect: absent or reduced phosphatase activity (Han et al., 2000; Rodriguez-Escudero et al., 2011; Mighell et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21828076, 25527629, 23335809, 30720243, 29625052, 24721394, 20533527, 23161105, 28526761, 17526800, 21659347, 26800850, 28201779, 28304377, 28984400, 16506206, 11875759, 20718038, 18986487, 29706350, 19265751, 24475377, 33482836, 36192478, 10866302)
Comment:
The missense variant p.R173H in PTEN (NM_000314.8) has been reported before both in a patient with developmental delay (Varga EA et al) as well as in patients with PTEN related hamartoma syndrome (Bubien et al; Hansen et al).Functional studies revealed reduced phosphatse activity (Rodriguez-Escudero et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic. The p.R173H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 173 of PTEN is conserved in all mammalian species. The nucleotide c.518 in PTEN is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant has been previously reported as a heterozygous change in patients with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 23335809, 20533527, 28526761). In vitro assays showed that this variant is associated with decreased phosphatase activity (PMID: 21828076, 10866302). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001 % (2/251148) and thus is presumed to be rare. The c.518G>A (p.Arg173His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.518G>A (p.Arg173His) variant is classified as Pathogenic.
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17526800, 18626099, 19265751, 20533527, 23335809].
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 173 of the PTEN protein (p.Arg173His). This variant is present in population databases (rs121913294, gnomAD 0.01%). This missense change has been observed in individuals with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 20533527, 23335809; Invitae). ClinVar contains an entry for this variant (Variation ID: 376032). 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 expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302). This variant disrupts the p.Arg173 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10866302, 17526800, 25669429, 28475857). 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.
Comment:
The p.R173H variant (also known as c.518G>A), located in coding exon 6 of the PTEN gene, results from a G to A substitution at nucleotide position 518. The arginine at codon 173 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with clinical features of PTEN-hamartoma tumor syndrome (Hansen-Kiss E et al. J. Med. Genet., 2017 07;54:471-478; Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Varga EA et al. Genet. Med., 2009 Feb;11:111-7; McBride KL et al. Autism Res, 2010 Jun;3:137-41; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; van der Velden JJ. et al. Int. J. Dermatol. 2008 Nov;47 Suppl 1:45-8). In one study, functional assays demonstrated that this alteration inactivates phosphastase activity (Han SY et al. Cancer Res., 2000 Jun;60:3147-51); however, in vivo yeast assays demonstrated partial phosphastase activity in another study (Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). Another study determined that p.R173H has an intermediate effect on regulating p53 and Gata3 levels compared to wild-type and nonsense alleles (Xu J et al. Transl Oncol, 2014 Apr;7:196-205.e1). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children. | Hansen-Kiss E | Journal of medical genetics | 2017 | PMID: 28526761 |
| Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. | Tatton-Brown K | American journal of human genetics | 2017 | PMID: 28475857 |
| KLLN epigenotype-phenotype associations in Cowden syndrome. | Nizialek EA | European journal of human genetics : EJHG | 2015 | PMID: 25669429 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Combined PTEN Mutation and Protein Expression Associate with Overall and Disease-Free Survival of Glioblastoma Patients. | Xu J | Translational oncology | 2014 | PMID: 24721394 |
| PIK3CA and PTEN gene and exon mutation-specific clinicopathologic and molecular associations in colorectal cancer. | Day FL | Clinical cancer research : an official journal of the American Association for Cancer Research | 2013 | PMID: 23633456 |
| High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. | Bubien V | Journal of medical genetics | 2013 | PMID: 23335809 |
| A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes. | Rodríguez-Escudero I | Human molecular genetics | 2011 | PMID: 21828076 |
| Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly. | McBride KL | Autism research : official journal of the International Society for Autism Research | 2010 | PMID: 20533527 |
| The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. | Varga EA | Genetics in medicine : official journal of the American College of Medical Genetics | 2009 | PMID: 19265751 |
| Two Children with macrocephaly, developmental delay, and PTEN mutation. | Schwab JG | Clinical pediatrics | 2009 | PMID: 18626099 |
| Skin abnormalities in individuals with macrocephaly: Cowden disease from a dermatologist's point of view. | van der Velden JJ | International journal of dermatology | 2008 | PMID: 18986487 |
| Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. | Lachlan KL | Journal of medical genetics | 2007 | PMID: 17526800 |
| Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. | Han SY | Cancer research | 2000 | PMID: 10866302 |
| PTEN mutations in gliomas and glioneuronal tumors. | Duerr EM | Oncogene | 1998 | PMID: 9619835 |
| http://docm.genome.wustl.edu/variants/ENST00000371953:c.518G>A | - | - | - | - |
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Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Oncogenic
criteria provided, single submitter
|
Jul 31, 2024 | RCV004668926.1 |
Submissions - Somatic
|
Oncogenicity
Help
The submitted oncogenicity 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) |
Tumor type
Help
The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Oncogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neoplasm
Affected status: unknown
Allele origin:
somatic
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094211.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
|
Comment:
The p.Arg173His variant has been reported in 4 individuals with clinical feature s of Cowden syndrome (Lachlan 2007, Mcbride 2010, Bubien 2013) and segregated wi th disease in 2 affected relatives from 2 different families (Lachlan 2007, Varg a 2004). In addition, it segregated with macrocephaly in 1 relative from a third family (McBride 2010). This variant has been identified in 1/10324 African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs121913294). This variant has been observed as a somatic mutation in t umors, including glioblastoma (Duerr 1998) and colorectal cancer (Day 2013). The p.Arg173His variant is associated with decreased protein activity in vitro (Han 2000, Rodriguez-Escudero 2011). However, these types of assays may not accurate ly represent biological function. In summary, although additional studies are re quired to fully establish its clinical significance, the p.Arg173His variant is likely pathogenic in an autosomal dominant manner.
Comment:
Published functional studies demonstrate a damaging effect: absent or reduced phosphatase activity (Han et al., 2000; Rodriguez-Escudero et al., 2011; Mighell et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21828076, 25527629, 23335809, 30720243, 29625052, 24721394, 20533527, 23161105, 28526761, 17526800, 21659347, 26800850, 28201779, 28304377, 28984400, 16506206, 11875759, 20718038, 18986487, 29706350, 19265751, 24475377, 33482836, 36192478, 10866302)
Comment:
The missense variant p.R173H in PTEN (NM_000314.8) has been reported before both in a patient with developmental delay (Varga EA et al) as well as in patients with PTEN related hamartoma syndrome (Bubien et al; Hansen et al).Functional studies revealed reduced phosphatse activity (Rodriguez-Escudero et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic. The p.R173H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 173 of PTEN is conserved in all mammalian species. The nucleotide c.518 in PTEN is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant has been previously reported as a heterozygous change in patients with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 23335809, 20533527, 28526761). In vitro assays showed that this variant is associated with decreased phosphatase activity (PMID: 21828076, 10866302). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001 % (2/251148) and thus is presumed to be rare. The c.518G>A (p.Arg173His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.518G>A (p.Arg173His) variant is classified as Pathogenic.
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17526800, 18626099, 19265751, 20533527, 23335809].
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 173 of the PTEN protein (p.Arg173His). This variant is present in population databases (rs121913294, gnomAD 0.01%). This missense change has been observed in individuals with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 20533527, 23335809; Invitae). ClinVar contains an entry for this variant (Variation ID: 376032). 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 expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302). This variant disrupts the p.Arg173 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10866302, 17526800, 25669429, 28475857). 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.
Comment:
The p.R173H variant (also known as c.518G>A), located in coding exon 6 of the PTEN gene, results from a G to A substitution at nucleotide position 518. The arginine at codon 173 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with clinical features of PTEN-hamartoma tumor syndrome (Hansen-Kiss E et al. J. Med. Genet., 2017 07;54:471-478; Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Varga EA et al. Genet. Med., 2009 Feb;11:111-7; McBride KL et al. Autism Res, 2010 Jun;3:137-41; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; van der Velden JJ. et al. Int. J. Dermatol. 2008 Nov;47 Suppl 1:45-8). In one study, functional assays demonstrated that this alteration inactivates phosphastase activity (Han SY et al. Cancer Res., 2000 Jun;60:3147-51); however, in vivo yeast assays demonstrated partial phosphastase activity in another study (Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). Another study determined that p.R173H has an intermediate effect on regulating p53 and Gata3 levels compared to wild-type and nonsense alleles (Xu J et al. Transl Oncol, 2014 Apr;7:196-205.e1). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for somatic classification of this variant
Help| There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs121913294 ...
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 20, 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.