ClinVar Miner

Submissions for variant NM_001199973.2(RPL36A-HNRNPH2):c.300+3411_300+3412del (rs869312389)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000627420 SCV000748416 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing The c.718_719delAA variant has been reported previously in association with Fabry disease using alternative nomenclature (Davies et al., 1994; Sueoka et al., 2015). The c.718_719delAA variant is not observed in large population cohorts (Lek et al., 2016). The deletion causes a frameshift starting with codon Lysine 240, changes this amino acid to a Glutamic Acid residue and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Lys240GlufsX9. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.718_719delAA as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000627420 SCV000854792 pathogenic not provided 2017-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780298 SCV000917460 pathogenic Fabry disease 2018-12-05 criteria provided, single submitter clinical testing Variant summary: GLA c.718_719delAA (p.Lys240GlufsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Gln250X, p.Arg301X, p.Arg332fsX7). The variant was absent in 178766 control chromosomes. c.718_719delAA has been reported in the literature in multiple individuals affected with Fabry Disease (Blanch_1996, Bono_2011, Germain_2002, Nakano_2013, Shimotori_2007). These data indicate that the variant is very likely to be associated with disease. Enzyme activity assessed in transfected COS-7 cells showed the variant to result in <10% normal enzyme activity, with no response to 1-deoxygalactonojirimycin treatment (Shimotori_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000780298 SCV000965023 pathogenic Fabry disease 2018-12-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys240Glufs*9) in the GLA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Fabry disease (PMID: 8069316, 18205205, 27560961, 24582695, 22551898). ClinVar contains an entry for this variant (Variation ID: 222371). Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.