ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.114C>T (p.Gly38=)

gnomAD frequency: 0.00001  dbSNP: rs2082632873
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Total submissions: 2
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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 RCV004596481 SCV005089679 likely pathogenic Deficiency of guanidinoacetate methyltransferase 2024-04-26 reviewed by expert panel curation The NM_000156.6:c.114C>T (p.Gly38=) variant in GAMT is a synonymous (silent) variant. The computational splicing predictor SpliceAI gives a score of 0.98 for donor gain, predicting that the variant activates a cryptic splice site within exon 1 of GAMT (PP3). This variant has been reported in an individual with GAMT deficiency (PMID: 37305710). This individual was compound heterozygous for this variant and a variant that has been classified as likely pathogenic variant by the ClinGen CCDS VCEP, c.328-1G>A (ClinVar ID 844968), and confirmed in trans by parental testing (PMID: 37305710). This individual had elevated guanidinoacetate levels in plasma and significantly decreased creatine peak on brain MRS (PP4_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1305363). In summary, this variant meets the criteria to be classified as likely pathogenic 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 1.1.0): PM2_Supporting, PM3, PP3, PP4_Strong. (Classification approved by the ClinGen CCDS VCEP on April 26, 2024)
GeneDx RCV001768570 SCV001992358 uncertain significance not provided 2019-02-08 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016)

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