ClinVar Miner

Submissions for variant NM_018136.5(ASPM):c.1138C>T (p.Gln380Ter)

dbSNP: rs587783215
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000145078 SCV000192119 pathogenic Microcephaly 5, primary, autosomal recessive 2013-02-08 criteria provided, single submitter clinical testing
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171162 SCV000221358 likely pathogenic not provided criteria provided, single submitter research
Baylor Genetics RCV000145078 SCV001522639 pathogenic Microcephaly 5, primary, autosomal recessive 2019-10-30 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity Omics RCV000145078 SCV002019640 pathogenic Microcephaly 5, primary, autosomal recessive 2022-06-28 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000145078 SCV002507044 pathogenic Microcephaly 5, primary, autosomal recessive 2022-05-04 criteria provided, single submitter curation The homozygous p.Gln380Ter variant in ASPM was identified by our study in 2 siblings with autosomal recessive primary microcephaly 5. The variant has been reported in 1 Middle Eastern individual with autosomal recessive primary microcephaly 5 (PMID: 23611254), but was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 157777) as pathogenic by Genetic Services Laboratory, University of Chicago and Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, and as likely pathogenic by Developmental Genetics Unit, King Faisal Specialist Hospital & Research Centre. This nonsense variant leads to a premature termination codon at position 380, which is predicted to lead to a truncated or absent protein. Loss of function of the ASPM gene is an established disease mechanism in autosomal recessive primary microcephaly 5. The presence of this variant in at least 2 homozygotes, and in 2 individuals with autosomal recessive primary microcephaly 5 increases the likelihood that the p.Gln380Ter variant is pathogenic (PMID: 23611254). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive primary microcephaly 5 based on the predicted impact of the variant, its absence from control populations, and its homozygous appearance in 3 affected individuals. ACMG/AMP Criteria applied: PVS1, PM2, PM3 (Richards 2015).
Genome-Nilou Lab RCV000145078 SCV004178771 pathogenic Microcephaly 5, primary, autosomal recessive 2023-04-11 criteria provided, single submitter clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV000145078 SCV001132965 pathogenic Microcephaly 5, primary, autosomal recessive 2019-08-25 no assertion criteria provided clinical testing

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