Submissions for variant NM_000169.3(GLA):c.370-532_1278del

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001261510	SCV001438807	pathogenic	Fabry disease	2020-09-16	criteria provided, single submitter	clinical testing	Variant summary: The variant identified by MLPA or other technology involves a large 4.5kb deletion that spans the entire length exons 3-6 and a majority of exon 7 in the GLA gene. A presumed nomenclature of c.370-532_1278del4521 has been designated for the purposes of this classification. A direct repeat AAG sequence is present at both deletion termini and the precise breakpoints are thought to have occurred immediately 5', 3' or within these direct repeats (Kornreich_1990). Some clinical labs have also reported this variant as 370-533_1277del. HGMD database (CG900355) calls this variant as c.370-530_1279del4520 citing Kornreich_1990. Therefore, although exact breakpoints of this deletion may vary, it is expected to result in a loss of protein function of the GLA gene product, a known mechanism of disease. The variant was absent in 183061 control chromosomes (gnomAD). This variant has been reported in the literature in an individual affected with Fabry Disease (Kornreich_1990 cites Bernstein_1989) and has been used as the primary evidence supporting this classification. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in the absence of any detectable alpha-galactosidase activity in plasma and/or cell sources from the affected hemizygote manifesting the classical Fabry disease phenotype (Bernstein_1989). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.