ClinVar Miner

Submissions for variant NM_001482.3(GATM):c.565C>T (p.Arg189Cys)

gnomAD frequency: 0.00001  dbSNP: rs377578020
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen RCV000810963 SCV003852685 uncertain significance Arginine:glycine amidinotransferase deficiency 2023-01-24 reviewed by expert panel curation The NM_001482.3:c.565C>T variant in GATM is a missense variant that is predicted to result in the substitution of arginine by cysteine at amino acid 189 (p.Arg189Cys). To our knowledge, this variant has not been reported in individuals with AGAT deficiency in the published literature. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/16246 alleles) in the African population (none of the population data codes are met). When overexpressed in HeLa cells, the variant resulted in <10% of wild-type enzyme activity (PMID: 27233232) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 225915). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PP3. (Classification approved by the ClinGen CCDS VCEP on January 24, 2023).
Labcorp Genetics (formerly Invitae), Labcorp RCV000810963 SCV000951205 uncertain significance Arginine:glycine amidinotransferase deficiency 2023-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 189 of the GATM protein (p.Arg189Cys). This variant is present in population databases (rs377578020, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with GATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 225915). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GATM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GATM function (PMID: 27233232). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002494552 SCV002792468 uncertain significance Arginine:glycine amidinotransferase deficiency; Fanconi renotubular syndrome 1 2022-02-19 criteria provided, single submitter clinical testing
Hospital for Sick Children RCV000488885 SCV000267664 not provided not provided no assertion provided in vitro

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