Renal tubulopathies

Gene: GATM

Green List (high evidence)

Comment on list classification: Changing rating from red to green as more than 3 cases reported.

Created: 4 Sep 2019, 9:38 p.m. | Last Modified: 4 Sep 2019, 9:38 p.m.

Panel Version: 1.119

Comment on mode of pathogenicity: All missense variants reported to date. In silico analysis suggests that the variants result in an additional interaction interface

Created: 4 Sep 2019, 9:38 p.m. | Last Modified: 4 Sep 2019, 9:38 p.m.

Panel Version: 1.118

PMID: 29654216 (Reichold et al 2018) reports 5 families with with a novel form of autosomal dominant kidney disease characterized by renal tubular Fanconi syndrome early in life followed by progression to renal glomerular failure in mid-adulthood. All patients show monoallelic mutations in the gene GATM. 4 heterozygous missense mutations of evolutionary conserved amino acid residues in GATM were found (c.958C>T, p.P320S; c.1006A>G, p.T336A; c.1007C>T, p.T336I; c.1022C>T, p.P341L). In each family, one variant segregated with the disorder and was fully penetrant. In silico analysis showed that the particular GATM mutations create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells.

Created: 30 Aug 2019, 3:40 p.m. | Last Modified: 4 Sep 2019, 9:35 p.m.

Panel Version: 1.116

This gene was part of an initial gene list collated by Emma Ashton (NE Thames Regional Genetics laboratory, GOSH NHS Foundation Trust) January 2019 on behalf of the GMS Renal Specialist Test Group; Gene Symbol submitted: GATM; Suggested initial gene rating: green; Evidence for inclusion: Reichold et al 2018 J Am Soc Nephrol 29(7): 1849-1858. PMID: 29654216Evidence for exclusion: none provided; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none provided; Other Comments: AR LoF mutations result in cerebral creatine deficiency syndrome. AD missense mutations in critical protein region lead to creation of an additional interaction surface and protein aggregates

Created: 3 Feb 2019, 11:32 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Renal fanconi syndrome and kidney failure (no MIM number); Cerebral creatine deficiency syndrome 3, MIM 612718 (AR)

Publications

• Reichold et al 2018 J Am Soc Nephrol 29(7): 1849-1858. PMID: 29654216

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments