Submissions for variant NM_018136.5(ASPM):c.4214G>A (p.Arg1405His)

gnomAD frequency: 0.00016  dbSNP: rs143092798

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000194113	SCV000246592	uncertain significance	not specified	2014-08-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000766839	SCV000590747	uncertain significance	not provided	2017-06-21	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ASPM gene. The R1405H variant has not been published in association with brain malformations to our knowledge. The R1405H variant is observed in 2/10258 (0.02%) alleles from individuals of African background, in the ExAC dataset and 1 homozygous individual undergoing testing at GeneDx (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1405H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Fulgent Genetics, Fulgent Genetics	RCV000763785	SCV000894697	uncertain significance	Microcephaly 5, primary, autosomal recessive	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000763785	SCV001522646	uncertain significance	Microcephaly 5, primary, autosomal recessive	2020-06-10	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	RCV000766839	SCV002267429	uncertain significance	not provided	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1405 of the ASPM protein (p.Arg1405His). This variant is present in population databases (rs143092798, gnomAD 0.01%). 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: 210356). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	RCV002517053	SCV003536534	uncertain significance	Inborn genetic diseases	2022-06-03	criteria provided, single submitter	clinical testing	The c.4214G>A (p.R1405H) alteration is located in exon 18 (coding exon 18) of the ASPM gene. This alteration results from a G to A substitution at nucleotide position 4214, causing the arginine (R) at amino acid position 1405 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000763785	SCV004178681	uncertain significance	Microcephaly 5, primary, autosomal recessive	2023-04-11	criteria provided, single submitter	clinical testing