Submissions for variant NM_018136.5(ASPM):c.7160_7161del (p.Ser2387fs)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145180	SCV000192229	pathogenic	Microcephaly 5, primary, autosomal recessive	2013-12-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514794	SCV002929494	pathogenic	not provided	2022-05-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 157867). This variant has not been reported in the literature in individuals affected with ASPM-related conditions. This variant is present in population databases (rs587783266, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ser2387Cysfs*14) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317099	SCV004021155	pathogenic	Autosomal recessive primary microcephaly	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: ASPM c.7160_7161delCT (p.Ser2387CysfsX14) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 1.2e-05 in 250328 control chromosomes (gnomAD). To our knowledge, no occurrence of c.7160_7161delCT in individuals affected with Primary microcephaly and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003407562	SCV004115332	likely pathogenic	ASPM-related disorder	2023-11-21	criteria provided, single submitter	clinical testing	The ASPM c.7160_7161delCT variant is predicted to result in a frameshift and premature protein termination (p.Ser2387Cysfs*14). To our knowledge, this variant has not been reported in the literature. It is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in ASPM are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Genome-Nilou Lab	RCV000145180	SCV004178588	likely pathogenic	Microcephaly 5, primary, autosomal recessive	2023-04-11	criteria provided, single submitter	clinical testing

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