Submissions for variant NM_001482.3(GATM):c.1007C>T (p.Thr336Ile)

dbSNP: rs1481334244

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV004596413	SCV002600083	uncertain significance	Arginine:glycine amidinotransferase deficiency	2022-06-06	reviewed by expert panel	curation	The NM_001482.3:c.1007C>T variant in GATM is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 366 (p.Thr336Ile). To our knowledge, this variant has not been reported in the literature in any individuals with AGAT deficiency. It has, however, been reported in a family with renal Fanconi syndrome (PMID 29654216). Thie variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.137 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). Another missense variant c.1006A>G (p.Thr336Ala) in the same codon has also been reported in a family with renal Fanconi syndrome but not AGAT deficiency (PMID 29654216). This variant has not met the criteria to be classified as pathogenic or likely pathogenic for AGAT deficiency by the ClinGen CCDS VCEP (PM5 not met). In summary, the c.1007C>T (p.Thr336Ile) variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
OMIM	RCV001174511	SCV001337650	pathogenic	Fanconi renotubular syndrome 1	2020-06-11	no assertion criteria provided	literature only