ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.372G>A (p.Leu124=)

gnomAD frequency: 0.00001  dbSNP: rs748762855
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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 RCV001127000 SCV005619900 uncertain significance Deficiency of guanidinoacetate methyltransferase 2024-10-08 reviewed by expert panel curation The NM_000156.6:c.372G>A variant in GAMT is a synonymous (silent) variant (p.Leu124=) for which SpliceAI predicts no impact on splicing (all scores <0.1) (BP4, BP7) To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0 is 0.000005933 (7/1179802 alleles) 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). There is a ClinVar entry for this variant (Variation ID: 891607). 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, BP7. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024).
Illumina Laboratory Services, Illumina RCV001127000 SCV001286262 uncertain significance Deficiency of guanidinoacetate methyltransferase 2018-01-13 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV001459474 SCV001663313 likely benign Cerebral creatine deficiency syndrome 2023-06-16 criteria provided, single submitter clinical testing

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