Submissions for variant NM_000027.4(AGA):c.301G>A (p.Ala101Thr)

gnomAD frequency: 0.00001  dbSNP: rs752914246

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001991347	SCV002283454	likely pathogenic	Aspartylglucosaminuria	2021-08-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with threonine at codon 101 of the AGA protein (p.Ala101Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs752914246, ExAC 0.01%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala101 amino acid residue in AGA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1722323, 10571008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AGA protein function. This variant has not been reported in the literature in individuals affected with AGA-related conditions.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004770356	SCV005381623	uncertain significance	not specified	2024-08-01	criteria provided, single submitter	clinical testing	Variant summary: AGA c.301G>A (p.Ala101Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.301G>A in individuals affected with Aspartylglucosaminuria and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1495375). Based on the evidence outlined above, the variant was classified as uncertain significance.