Submissions for variant NM_018136.5(ASPM):c.8741T>C (p.Ile2914Thr)

gnomAD frequency: 0.00021  dbSNP: rs200856894

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145220	SCV000192271	uncertain significance	Microcephaly 5, primary, autosomal recessive	2013-02-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000145220	SCV000352637	uncertain significance	Microcephaly 5, primary, autosomal recessive	2018-01-12	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.
GeneDx	RCV000609920	SCV000726638	likely benign	not specified	2018-01-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857498	SCV002123935	uncertain significance	not provided	2022-04-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2914 of the ASPM protein (p.Ile2914Thr). This variant is present in population databases (rs200856894, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Seckel syndrome (PMID: 23611254). ClinVar contains an entry for this variant (Variation ID: 157899). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV002512567	SCV003692211	uncertain significance	Inborn genetic diseases	2021-06-25	criteria provided, single submitter	clinical testing	The c.8741T>C (p.I2914T) alteration is located in exon 18 (coding exon 18) of the ASPM gene. This alteration results from a T to C substitution at nucleotide position 8741, causing the isoleucine (I) at amino acid position 2914 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.