Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193068 | SCV001361650 | pathogenic | Fabry disease | 2021-03-23 | criteria provided, single submitter | clinical testing | Variant summary: GLA c.894T>A (p.Asn298Lys) results in a non-conservative amino acid change located in the Aldolase-type TIM barrel domain (IPR013785) of the encoded protein sequence. A different nucleotide change, namely c.894T>G that results in the same amino acid change, p.Asn298Lys has been reported in the HGMD and locus specific databases and in patients with Fabry disease. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183457 control chromosomes. Most ascertained publications do not specify the exact nucleotide change and are limited to reporting the underlying protein designation, namely p.Asn298Lys. Therefore, reports of patients with p.Asn298Lys, regardless of the specific nucleotide change were ascertained in the context of this evaluation. p.Asn298Lys (p.N298K) has been reported in the literature in individuals affected with Fabry Disease (example, Ashton-Prolla_2000, Sadick_2007, Cheung_2012, Boyd_2013, Sigmundsdottir_2014, Galanos_2002). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal alpha-galactosidase enzyme activity (example, Sadick_2007, Benjamin_2017). 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. |