TRPM7

Inheritance Pattern: AD

Disease ID:MONDO:0015372

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0011176

Submitter: ClinGen

The *TRPM7* gene is located on chromosome 15q.21.2 at chr15:50,552,473-50,686,797 (GRCh38/hg38) and encodes the protein Transient Receptor Potential cation channel, subfamily M, member 7. This is a bifunctional protein involved in the homeostatic regulation of intracellular Ca2+, Mg2+, and Zn2+, as well as trace metal concentrations. It also has Ser-Thr alpha-kinase activity that phosphorylates downstream substrates. This gene is associated with Hypomagnesemia with secondary hypocalcemia (HSH) (OMIM: 602014) with an autosomal dominant mode of inheritance. It has also been associated with seizures and developmental delay which may be related to the hypomagnesemia. The associations with macrothrombocytopenia and migraine were not investigated here and evidence from platelet studies were not included. The preferred disease name suggested for this disorder is Hypomagnesemia with secondary hypocalcemia. *TRPM7* was first reported in relation to autosomal dominant Hypomagnesemia with secondary hypocalcemia in 2022 (PMID: 35561741). Three members of two generations of a French family presented with a low serum Mg2+ and low urinary Mg2+ excretion. All three had an abnormal Mg2+ loading test with defective intestinal and renal Mg reabsorption that was the same as seen in patients with loss-of-function defects in TRPM6. The mechanism of pathogenicity for these mutations in *TRPM7* is loss-of-function. At least five variants (missense and canonical splicing) that have been reported in six probands in two publications (PMIDs: 35561741; 39099503) are included in this curation. A total of 5.5/12 points for genetic evidence was reached. This gene-disease relationship is also supported by functional studies: expression, biochemical function and protein interaction (PMIDs: 12887921; 16150690; 35561741; 39099563). A total of 1.5/6 points for experimental evidence was reached. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date February 5th, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0018100

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0031447

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0054866

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014631

Submitter: Ambry Genetics

Inheritance Pattern: Unknown

Disease ID:MONDO:0007104

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0031447

Submitter: ClinGen

The TRPM7 gene encodes for the transient receptor potential cation channel, subfamily M, member 7, a ubiquitously expressed bifunctional protein comprising a transient receptor potential channel segment linked to a cytosolic α-type serine/threonine protein kinase domain. TRPM7 forms a constitutively active Mg2+ and Ca2+ permeable channel, which regulates diverse cellular processes including cell cycle, apoptosis, and cell death. TRPM7 is expressed in platelets and megakaryocytes and plays a role in proplatelet formation and platelet activation. Its channel activity is crucial for proplatelet formation while its kinase activity is crucial for platelet activation. Three patients with variants in TRPM7 have been described: two with macrothrombocytopenia and one with impaired platelet aggregation (PMID: 27020697). Therefore, the defect related to TRPM7 gene variants is not exclusively an inherited thrombocytopenia or an inherited platelet function disorder, it is possible that it could depend on which domain is mutated. Indeed, if the channel domain is compromised patients show macrothrombocytopenia, because NMMIIA is a downstream effector of TRPM7, in particular Mg2+ inhibits NMMIIA activity, and dysfunctional TRPM7 cause increased activity of NMMIIA that is associated with impaired proplatelet formation. On the other hand, the patient without macrothrombocytopenia but impaired platelet aggregation carries a variant in the kinase domain of TRPM7 (p.G1353D). Interestingly, in line with this phenotype, one study demonstrated that the kinase domain of TRPM7 is crucial for platelet activation and platelet aggregation (PMID:29146750) Evidences supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (biochemical functions; expression; functional alteration in non-patient cells, non-human model organisms). Summary of Case Level Data: 1.1 POINTS Variants in this gene have been reported in 3 probands in 1 publication (PMID: 27020697). Summary of Experimental Data: 5.5 POINTS Schmitz et al (PMID: 12887921) showed that TRPM7 is a channel for Mg 2+ (Experimental evidence - Biochemical Function). Stritt et al (PMID: 27020697) showed that the mRNA for TRPM7 is expressed in mouse platelets and mouse megakaryocytes (Experimental evidence Expression in cells relevant for the disease). The same authors also performed patch clamp studies on HEK293 cells confirming that two different TRPM7 variants reduced TRPM7 channel activity (Experimental evidence - Functional Alteration Non-patient cells) (PMID: 27020697). Megakaryocyte and platelet specific TRPM7 KO mice (Trpm7fl/fl-Pf4Cre) show several abnormalities in megakaryocytes, including aberrant Mg2+ and Ca2+ homeostasis as well as dysregulated actomyosin complexes, resulting in impaired platelet production and macrothrombocytopenia in mice (PMID: 27020697) (Model Systems Non-human model organism), showing the same phenotype of patients with mutations in the channel domain. Mice with mutant TRPM7 kinase domain show impaired platelet aggregation and activation (PAC-1 binding and P-selectin exposure), in line with the phenotype of the patients with a variant in the kinase domain (PMID: 29146750) (Model Systems Non-human model organism). In summary, with 6.6 points, we obtained moderate association of TRPM7 with the disorder related to TRPM7 gene variants. This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on 2024 Jun 03 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0007104

Submitter: PanelApp Australia