ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.410A>C (p.Tyr137Ser)

gnomAD frequency: 0.00001  dbSNP: rs1131691930
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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 RCV003159126 SCV003852722 uncertain significance Deficiency of guanidinoacetate methyltransferase 2023-02-03 reviewed by expert panel curation The NM_000156.6:c.410A>C variant in GAMT is a missense variant that is predicted to result in the substitution of tyrosine by serine at amino acid 137 (p.Tyr137Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 (1/8680 alleles) in the African population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in an individual with GAMT deficiency in the published literature and the result of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 430374). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3.
GeneDx RCV000493730 SCV000583166 likely pathogenic not provided 2024-12-13 criteria provided, single submitter clinical testing Observed with a second GAMT variant in a patient with epileptic encephalopathy, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 29655203); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29655203)
Labcorp Genetics (formerly Invitae), Labcorp RCV001303060 SCV001492293 uncertain significance Cerebral creatine deficiency syndrome 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 137 of the GAMT protein (p.Tyr137Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with epilepsy and neurodevelopmental disorders (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 430374). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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