ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.518G>A (p.Arg173His) (rs121913294)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484180 SCV000566605 pathogenic not provided 2017-12-27 criteria provided, single submitter clinical testing This pathogenic variant is denoted PTEN c.518G>A at the cDNA level, p.Arg173His (R173H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been observed in multiple individuals with findings consistent with PTEN Hamartoma Tumor syndrome (Lachlan 2007, Varga 2009, McBride 2010, Bubien 2013, Hansen-Kiss 2017). Functional studies have shown that this variant results in reduced phosphatase activity (Han 2000, Rodriguez-Escudero 2011). PTEN Arg173His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Phosphatase domain (Wang 2008). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the current evidence, we consider PTEN Arg173His to be pathogenic.
Herman Laboratory,Nationwide Children's Hospital RCV000490595 SCV000579279 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
Invitae RCV000490595 SCV000645595 pathogenic PTEN hamartoma tumor syndrome 2020-09-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 173 of the PTEN protein (p.Arg173His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121913294, ExAC 0.01%). This variant has been reported in individuals and families affected with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 20533527, 23335809, Invitae database). ClinVar contains an entry for this variant (Variation ID: 376032). Experimental studies in E. coli have shown that this missense change abolishes the phosphatase activity of the PTEN protein (PMID: 10866302). A different missense substitution at this codon (p.Arg173Cys) has been determined to be pathogenic (PMID: 10866302, 17526800, 25669429, 28475857). This suggests that the arginine residue is critical for PTEN protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000490595 SCV000711962 likely pathogenic PTEN hamartoma tumor syndrome 2016-10-20 criteria provided, single submitter clinical testing 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000484180 SCV001334626 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000432256 SCV000504815 likely pathogenic Neoplasm of brain 2015-07-14 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000484180 SCV000692014 pathogenic not provided no assertion criteria provided clinical testing

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