ClinVar Miner

Submissions for variant NM_001482.3(GATM):c.541G>A (p.Glu181Lys)

dbSNP: rs376982466
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Total submissions: 3
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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 RCV001201875 SCV003852686 uncertain significance Arginine:glycine amidinotransferase deficiency 2023-01-24 reviewed by expert panel curation The NM_001482.3:c.541G>A variant in GATM is a missense variant that is predicted to result in the substitution of glutamine by lysine at amino acid 181 (p.Glu181Lys). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00001 (1/113714 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in <15% wild-type enzyme activity (PMID: 27233232). The computational predictor REVEL gives a score of 0.608, which neither predicts a damaging nor a benign inpact on AGAT function. To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. There is a ClinVar entry for this variant (Variation ID: 225914). 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, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on January 24, 2023).
Labcorp Genetics (formerly Invitae), Labcorp RCV001201875 SCV001372966 uncertain significance Arginine:glycine amidinotransferase deficiency 2023-10-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 181 of the GATM protein (p.Glu181Lys). This variant is present in population databases (rs376982466, gnomAD 0.0009%). 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: 225914). 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. 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.
Hospital for Sick Children RCV000488903 SCV000267663 not provided not provided no assertion provided in vitro

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