ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.274A>G (p.Asn92Asp)

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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 RCV003159287 SCV003852703 likely pathogenic Deficiency of guanidinoacetate methyltransferase 2024-09-11 reviewed by expert panel curation The NM_000156.6:c.274A>G variant in GAMT is a missense variant predicted to cause the substitution of an asparagine by an aspartate at amino acid position 92 (p.Asn92Asp). This variant has been previously reported in one individual with elevated urine guanidinoacetate and low urine creatine (PP4) who was homozygous for the variant (PMID: 19288536, 24415674, 33996490) (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001705 (2/1172782 alleles; no homozygotes) in the European non-Finnish 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 0.92, evidence that correlates with impact to GAMT function (PP3_Moderate applied for REVEL score range 0.773-0.932). This variant was shown to result in <15% GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 2446453). 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 2.0.0): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3_Moderate, PP4. (Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024).
Baylor Genetics RCV003159287 SCV004198595 likely pathogenic Deficiency of guanidinoacetate methyltransferase 2023-04-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV003159287 SCV005655118 likely pathogenic Deficiency of guanidinoacetate methyltransferase 2024-01-03 criteria provided, single submitter clinical testing

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