ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.182G>A (p.Gly61Glu) (rs77168423)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000289407 SCV000410915 likely benign Deficiency of guanidinoacetate methyltransferase 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx RCV000480090 SCV000569738 uncertain significance not provided 2018-08-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the GAMT gene. The G61E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 29/16548 (0.2%) alleles from individuals of East Asian background in large population cohorts (Lek et al., 2016). The G61E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000550292 SCV000659563 uncertain significance Cerebral creatine deficiency syndrome 2019-05-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 61 of the GAMT protein (p.Gly61Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs77168423, ExAC 0.4%). This variant has not been reported in the literature in individuals with GAMT-related disease. ClinVar contains an entry for this variant (Variation ID: 328350). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Natera, Inc. RCV000289407 SCV001460088 uncertain significance Deficiency of guanidinoacetate methyltransferase 2020-01-07 no assertion criteria provided clinical testing

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