Submissions for variant NM_000156.6(GAMT):c.299G>A (p.Arg100Gln)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV004823093	SCV005619903	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2024-10-08	reviewed by expert panel	curation	The NM_000156.6:c.299G>A variant in GAMT is a missense variant that is predicted to cause the substitution of an arginine by a glutamine at amino acid position 100 (p.Arg100Gln). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003629 (2/55112 alleles) in the Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.203 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function. SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 2145645). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003065136	SCV003453507	uncertain significance	Cerebral creatine deficiency syndrome	2022-03-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 100 of the GAMT protein (p.Arg100Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GAMT-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV003274188	SCV003985177	likely benign	Inborn genetic diseases	2023-05-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.