FXYD2 was first reported in relation to autosomal dominant renal hypomagnesemia 2 in 2000 (Meij et al. 2000, PMID: 11062458). The gene is associated with low magnesium levels due to a loss of kidney magnesium, as well as hypokalemia, hypocalciuria, and renal failure. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no relevant differences in molecular mechanism, inheritance pattern or phenotypic variability (there is only one disease assertion for this gene). Therefore, no pre-curation was needed. One variant (the missense variant Gly41Arg) has been reported in 18 probands from one family in 2 publications (PMIDs: 25765846, 11062458) included in this curation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by experimental evidence (biochemical functional evidence, expression level data, functional alteration evidence, and a mouse model; PMIDs: 18787637, 18448590, 18448590, 15755730). In summary, FXYD2 is moderately associated with autosomal dominant renal hypomagnesemia 2. The disease is only associated with one variant in the gene, but there is case-level data (including lots of segregation) and various experimental evidence to support the relationship. Thus, a moderate classification, which was reached based on the point system (7.0 points were reached), felt appropriate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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