ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.278A>G (p.His93Arg) (rs121909238)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000645075 SCV000886857 pathogenic PTEN hamartoma tumor syndrome 2018-11-28 reviewed by expert panel curation PTEN c.278A>G (p.His93Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor(s) ClinVar Organization ID: 26957) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM2: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 26579216, 25647146, 20718038, 21828076, 29373119, 29785012, 29706350) PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 15805158, internal laboratory contributor(s) ClinVar Organization ID: 26957)
Invitae RCV000645075 SCV000766817 uncertain significance PTEN hamartoma tumor syndrome 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 93 of the PTEN protein (p.His93Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with symptoms consistent with PTEN hamartoma tumor syndrome (PMID: 24345843), as well as, individuals affected with macrocephaly and autism including one individual in whom the variant was de novo (PMID: 15805158, 25647146). ClinVar contains an entry for this variant (Variation ID: 7848). Experimental studies have shown that this missense variant reduces phosphatase catalytic activity, alters lipid membrane binding, and reduces the PTEN protein inhibitory effect on tyrosine hydroxylase (PMID: 20718038, 21828076, 25647146, 22505997, 26579216). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
OMIM RCV000008298 SCV000028505 pathogenic Macrocephaly/autism syndrome 2005-04-01 no assertion criteria provided literature only

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