ClinVar Miner

Submissions for variant NM_018136.5(ASPM):c.9178C>T (p.Gln3060Ter)

gnomAD frequency: 0.00015  dbSNP: rs137852994
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000005248 SCV000192278 pathogenic Microcephaly 5, primary, autosomal recessive 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000214564 SCV000278803 pathogenic not provided 2022-03-21 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 23611254, 15355437, 30086807, 19028728)
Athena Diagnostics RCV000214564 SCV000840899 pathogenic not provided 2018-05-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193347 SCV001362104 pathogenic Autosomal recessive primary microcephaly 2019-08-07 criteria provided, single submitter clinical testing Variant summary: ASPM c.9178C>T (p.Gln3060X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 249856 control chromosomes (gnomAD). c.9178C>T has been reported in the literature in individuals affected with Primary autosomal recessive microcephaly (e.g. Kumar_2004). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000005248 SCV002019651 pathogenic Microcephaly 5, primary, autosomal recessive 2020-10-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000214564 SCV002230153 pathogenic not provided 2025-01-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln3060*) in the ASPM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASPM are known to be pathogenic (PMID: 19028728, 23611254). This variant is present in population databases (rs137852994, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with primary microcephaly (PMID: 15355437, 19028728, 23611254). ClinVar contains an entry for this variant (Variation ID: 4960). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000005248 SCV004177558 pathogenic Microcephaly 5, primary, autosomal recessive 2023-04-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV004955250 SCV005495836 pathogenic Inborn genetic diseases 2024-11-20 criteria provided, single submitter clinical testing The c.9178C>T (p.Q3060*) alteration, located in exon 21 (coding exon 21) of the ASPM gene, consists of a C to T substitution at nucleotide position 9178. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/281152) total alleles studied. The highest observed frequency was 0.014% (5/35320) of Latino alleles. This variant has been identified in the homozygous state in individuals with features consistent with ASPM-related microcephaly (Tan, 2014; Kumar, 2004). Based on the available evidence, this alteration is classified as pathogenic.
OMIM RCV000005248 SCV000025426 pathogenic Microcephaly 5, primary, autosomal recessive 2004-10-01 no assertion criteria provided literature only
GeneReviews RCV000005248 SCV000041397 not provided Microcephaly 5, primary, autosomal recessive no assertion provided literature only

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