Submissions for variant NM_001099922.3(ALG13):c.3130G>A (p.Ala1044Thr) (rs1064796719)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482872	SCV000573732	uncertain significance	not provided	2018-05-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ALG13gene. The A1044T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A1044T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A1044T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter 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.
Invitae	RCV000549460	SCV000652516	uncertain significance	Epileptic encephalopathy, early infantile, 36	2018-03-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with threonine at codon 861 of the ALG13 protein (p.Ala861Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ALG13-related disease. ClinVar contains an entry for this variant (Variation ID: 423965). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.