Submissions for variant NM_000314.8(PTEN):c.1004G>A (p.Arg335Gln)

dbSNP: rs1085308040

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Herman Laboratory, Nationwide Children's Hospital	RCV000490592	SCV000579259	pathogenic	PTEN hamartoma tumor syndrome	2017-03-01	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001799513	SCV002043787	likely pathogenic	Macrocephaly-autism syndrome		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490592	SCV002225547	uncertain significance	PTEN hamartoma tumor syndrome	2023-11-24	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002404284	SCV002713677	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	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.
All of Us Research Program, National Institutes of Health	RCV000490592	SCV004835546	uncertain significance	PTEN hamartoma tumor syndrome	2023-11-20	criteria provided, single submitter	clinical testing	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.
Solve-RD Consortium	RCV004767301	SCV005091343	likely pathogenic	Familial meningioma	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team