ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.131G>A (p.Gly44Asp)

dbSNP: rs1085308042
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Herman Laboratory, Nationwide Children's Hospital RCV000490575 SCV000579261 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001092593 SCV001249156 pathogenic not provided 2019-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003492073 SCV004241993 pathogenic Cowden syndrome 2023-12-08 criteria provided, single submitter clinical testing Variant summary: PTEN c.131G>A (p.Gly44Asp) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain (IPR003595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251050 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.131G>A has been reported in the literature in individuals affected with Cowden Syndrome and macrocephaly (e.g., Varga_2009, Tatton-Brown_2017, Gabriel_2022), including at least once as a de novo occurrence (e.g., Tatton-Brown_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant resulted in an approximately 88% reduction in PIP3 phosphatase activity relative to wild type in an in vivo functional assay in yeast (e.g., Rodriguez-Escudero_2011). The following publications have been ascertained in the context of this evaluation (PMID: 34958143, 21828076, 28475857, 19265751). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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