ClinVar Miner

Submissions for variant NM_018136.5(ASPM):c.2195T>C (p.Leu732Ser)

gnomAD frequency: 0.00001  dbSNP: rs587783224
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000145094 SCV000192137 benign not specified 2013-02-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV002512565 SCV003618869 uncertain significance Inborn genetic diseases 2022-06-17 criteria provided, single submitter clinical testing The c.2195T>C (p.L732S) alteration is located in exon 6 (coding exon 6) of the ASPM gene. This alteration results from a T to C substitution at nucleotide position 2195, causing the leucine (L) at amino acid position 732 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV003329242 SCV004037022 uncertain significance not provided 2023-03-19 criteria provided, single submitter clinical testing Reported previously with a frameshift and a missense ASPM variant in a patient with primary microcephaly, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes; the authors interpreted this missense variant as a likely normal variant (Tan et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; This variant is associated with the following publications: (PMID: 33937237, 23611254)
Labcorp Genetics (formerly Invitae), Labcorp RCV003329242 SCV004622473 uncertain significance not provided 2024-03-04 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 732 of the ASPM protein (p.Leu732Ser). This variant is present in population databases (rs587783224, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with ASPM-related conditions. ClinVar contains an entry for this variant (Variation ID: 157791). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ASPM protein function with a negative predictive value of 80%. 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.

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