Submissions for variant NM_000169.3(GLA):c.1072_1074del (p.Glu358del)

dbSNP: rs730880453

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157903	SCV000207834	pathogenic	not provided	2023-09-06	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 27657681); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18154965, 30116053, 30386727, 12428061, 12512750, 11804208, 15339079, 31956509, 31509825, 28340691, 26415523, 24386359, 21598360, 16595074, 15712228, 26297554, 10666480, 32714835, 32843101, 8807334, 27657681, 33437642, 18698230)
Eurofins Ntd Llc (ga)	RCV000157903	SCV000339433	pathogenic	not provided	2017-08-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815405	SCV000955856	pathogenic	Fabry disease	2023-10-12	criteria provided, single submitter	clinical testing	This variant, c.1072_1074del, results in the deletion of 1 amino acid(s) of the GLA protein (p.Glu358del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Fabry disease (PMID: 8807334, 15339079, 15712228, 15713906, 18154965, 26297554). ClinVar contains an entry for this variant (Variation ID: 180844). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the p.Glu358 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452068, 12428061, 16595074, 21598360, 24386359, 25382311, 26297554, 26415523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000815405	SCV001361588	pathogenic	Fabry disease	2020-11-03	criteria provided, single submitter	clinical testing	Variant summary: GLA c.1072_1074delGAG (p.Glu358del) results in an in-frame deletion that is predicted to remove a Glutamate amino acid from the C-terminal beta-sandwich domain (IPR035373) of the encoded protein. The variant was absent in 183351 control chromosomes (gnomAD). c.1072_1074delGAG has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Blanch_1996, Topaloglu_1999, Wu_2004, Schafer_2005, Monserrat_2007, Shin_2008, Sawada_2020, Hongo_2020). These data indicate that the variant is very likely to be associated with disease. These publications also reported alpha-galactosidase activity values, and demonstrated significantly reduced GLA activity in both patient derived samples and in in vitro studies, furthermore the enzyme activity was shown to be non-responsive to 1-deoxygalactonojirimycin (DGJ) treatment (Shin_2008). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000157903	SCV002018449	likely pathogenic	not provided	2020-08-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000815405	SCV002054375	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing