Submissions for variant NM_000169.3(GLA):c.413G>A (p.Gly138Glu)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001217560	SCV001389406	pathogenic	Fabry disease	2020-07-15	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Fabry disease (PMID: 30380558, 15091117, 15713906, 30762167). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Gly138 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 9100224, 15713906, 30380558, 15091117), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine with glutamic acid at codon 138 of the GLA protein (p.Gly138Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001217560	SCV001554592	pathogenic	Fabry disease	2021-03-24	criteria provided, single submitter	clinical testing	Variant summary: GLA c.413G>A (p.Gly138Glu) 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 was absent in 183467 control chromosomes (gnomAD). c.413G>A has been reported in the literature in multiple individuals/families affected with Fabry Disease (e.g. Germain_2002, Ries_2005, Wu_2011, Lin_2018). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant results in absent or very low enzyme activity (e.g. Ries_2005, Wu_2011). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001780137	SCV002018443	likely pathogenic	not provided	2019-06-16	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001217560	SCV002054437	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing

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