ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.439C>T (p.His147Tyr)

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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 RCV003159294 SCV003852717 likely pathogenic Deficiency of guanidinoacetate methyltransferase 2023-03-23 reviewed by expert panel curation The NM_000156.6:c.439C>T (p.His147Tyr) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID: 24415674). This variant was identified in 0.001470% (1/68016) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, dbSNP ID: rs1371496558) (PM2_Supporting). The patient previously reported was a compound heterozygote that carried a reported pathogenic variant, c.11_36dup (p.Gly13fs, ClinVar Variation ID: 858462), in unknown phase (PM3_Supporting). This individual showed reduced GAMT enzyme activity in fibroblasts (PP4_Moderate). The p.His147Tyr variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.888). This variant was shown to result in 4% of wild-type enzyme activity in GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3, PP4_Moderate (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023)
Baylor Genetics RCV003159294 SCV004198604 likely pathogenic Deficiency of guanidinoacetate methyltransferase 2022-11-16 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003928960 SCV004738714 likely pathogenic GAMT-related disorder 2024-03-01 no assertion criteria provided clinical testing The GAMT c.439C>T variant is predicted to result in the amino acid substitution p.His147Tyr. This variant was reported in the compound heterozygous state with an early termination change in an individual with autosomal recessive cerebral creatine deficiency syndrome 2; and functional studies supported its pathogenicity (Mercimek-Mahmutoglu et al 2014. PubMed ID: 24415674). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.

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