ClinVar Miner

Submissions for variant NM_005465.7(AKT3):c.1082A>G (p.Glu361Gly)

gnomAD frequency: 0.00008  dbSNP: rs760280114
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Brain Malformations Variant Curation Expert Panel RCV001837027 SCV001949961 likely benign Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes 2022-02-11 reviewed by expert panel curation The c.1082A>G (NM_005465.7) variant in AKT3 is a missense variant predicted to cause substitution of (p.Glu361Gly). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001929 in the Ashkenazi Jewish population, which is higher than the ClinGen BMEP threshold (>=0.00185) for BA1, and therefore meets this criterion (BA1). AKT3, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant resides within the catalytic kinase domain of AKT3 which is defined as a critical functional domain by the ClinGen BMEP (PMID: 28969385) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: BA1, PP2, PM1_P; -6 points (VCEP specifications version 1; Approved: 1/31/2021)
Invitae RCV002073379 SCV002371314 likely benign Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 2022-02-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV002539734 SCV003755585 likely benign Inborn genetic diseases 2022-10-07 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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