Submissions for variant NM_018136.5(ASPM):c.2365A>G (p.Ile789Val)

gnomAD frequency: 0.00011  dbSNP: rs755203240

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724317	SCV000231756	uncertain significance	not provided	2015-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000220076	SCV000278793	uncertain significance	not specified	2017-08-25	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ASPM gene. The I789V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I789V variant is observed in 3/11476 (0.03%) alleles from individuals of Latino background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server)]. The I789V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. Additionally, most pathogenic variants that have been reported in this gene are truncating/loss of function. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Baylor Genetics	RCV001335896	SCV001529152	uncertain significance	Microcephaly 5, primary, autosomal recessive	2018-11-16	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV001335896	SCV002790406	uncertain significance	Microcephaly 5, primary, autosomal recessive	2021-09-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724317	SCV003511966	uncertain significance	not provided	2022-05-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 789 of the ASPM protein (p.Ile789Val). This variant is present in population databases (rs755203240, gnomAD 0.05%). 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: 198227). 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: "Tolerated"; 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.
Genome-Nilou Lab	RCV001335896	SCV004178724	uncertain significance	Microcephaly 5, primary, autosomal recessive	2023-04-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004668834	SCV005166494	uncertain significance	Inborn genetic diseases	2024-03-31	criteria provided, single submitter	clinical testing	The c.2365A>G (p.I789V) alteration is located in exon 6 (coding exon 6) of the ASPM gene. This alteration results from a A to G substitution at nucleotide position 2365, causing the isoleucine (I) at amino acid position 789 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.