Submissions for variant NM_018136.5(ASPM):c.5452C>T (p.Arg1818Cys)

gnomAD frequency: 0.00095  dbSNP: rs41299625

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145145	SCV000192193	uncertain significance	Microcephaly 5, primary, autosomal recessive	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000726692	SCV000279753	uncertain significance	not provided	2023-12-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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: 19770472, 12355089, 23611254)
Illumina Laboratory Services, Illumina	RCV000145145	SCV000352689	uncertain significance	Microcephaly 5, primary, autosomal recessive	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga)	RCV000726692	SCV000702127	uncertain significance	not provided	2018-06-11	criteria provided, single submitter	clinical testing
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000145145	SCV000804444	uncertain significance	Microcephaly 5, primary, autosomal recessive	2017-06-28	criteria provided, single submitter	provider interpretation	This 8 year old female with microcephaly (<2nd percentile) and intellectual disbality was found to carry a paternally inherited variant in the ASPM gene. The p.Arg1818Cys is present at 0.11% in the gnomAD dataset. Computational models predict the variant to be damaging. The patient also carries a maternally inherited ASPM variant (p.Leu2306SerfsX20), classified as a likely pathogenic. While homozygous or compound heterozygous variants in this gene are associated with autosomal recessive primary microcephaly, this patient also carries a maternally-inherited, pathogenic variant in KIF11, which is currently thought to be the underlying genetic etiology for her microcephaly and intellectual disability.
CeGaT Center for Human Genetics Tuebingen	RCV000726692	SCV001335215	uncertain significance	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000145145	SCV001529806	uncertain significance	Microcephaly 5, primary, autosomal recessive	2018-12-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726692	SCV002295375	uncertain significance	not provided	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1818 of the ASPM protein (p.Arg1818Cys). This variant is present in population databases (rs41299625, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with primary microcephaly (PMID: 23611254). ClinVar contains an entry for this variant (Variation ID: 157834). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASPM protein function. 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.
Genome-Nilou Lab	RCV000145145	SCV004178639	uncertain significance	Microcephaly 5, primary, autosomal recessive	2023-04-11	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000726692	SCV005187124	uncertain significance	not provided		criteria provided, single submitter	not provided
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252168	SCV001427918	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905250	SCV004719997	likely benign	ASPM-related disorder	2020-01-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).