ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.1118G>A (p.Gly373Asp) (rs869312227)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236260 SCV000292733 pathogenic not provided 2018-02-21 criteria provided, single submitter clinical testing The G373D mutation in the GLA gene has been reported previously in one male individual with Fabry disease (Germain D et al., 2001). G373D results in a non-conservative amino acid substitution at a position that is conserved in mammalian species. In addition, in vitro functional studies show that G373D results in loss of enzyme activity (Lukas J et al., 2013). Mutations in the same residue (G373R, G373S) and in nearby residues (L372R, L372P, L372Q, A377D) have been reported in the Human Gene Mutation Database in association with Fabry disease (Stenson P et al., 2014), further supporting the functional importance of this residue and region of the protein. Furthermore, the G373D mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000236260 SCV000336543 pathogenic not provided 2015-10-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193638 SCV001362606 pathogenic Fabry disease 2019-04-23 criteria provided, single submitter clinical testing Variant summary: GLA c.1118G>A (p.Gly373Asp) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183441 control chromosomes. c.1118G>A has been reported in the literature in individuals affected with Fabry Disease, in one case as a de novo occurrence (Shabbeer_2002, Germain_2001, Yoshimitsu_2011). An in vitro study reported the variant to have absent alpha Gal A activity and was not responsive to the pharmacological chaperone 1-deoxygalactonojirimycin (DGJ) (Lukas_2013). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. In addition, variants affecting the same codon, G373R, G373S, and nearby, L372R, L372P, L372Q, and A377D, have been reported in affected individuals via HGMD, therefore, suggesting the region is important for protein function. Based on the evidence outlined above, the variant was classified as pathogenic.

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