Submissions for variant NM_000156.6(GAMT):c.650C>T (p.Pro217Leu)

gnomAD frequency: 0.00003  dbSNP: rs139890971

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001833116	SCV002600167	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2022-06-06	reviewed by expert panel	curation	The NM_000156.6:c.650C>T variant in GAMT is a missense variant predicted to result in the substitution of proline for leucine at amino acid 217 (p.Pro217Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00008 (2/24536 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). The computational predictor REVEL gives a score of 0.745 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.5) impact on GAMT function. To our knowledge, this variant has not been reported in published literature in individuals with GAMT deficiency, and the results of functional studies are unavailable. This variant has been previously reported in ClinVar (Variation ID: 205592). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
GeneDx	RCV000725402	SCV000241171	uncertain significance	not provided	2024-05-31	criteria provided, single submitter	clinical testing	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; Has not been previously published in a peer reviewed journal to our knowledge; This variant is associated with the following publications: (PMID: Di Muro2019[Thesis])
Eurofins Ntd Llc (ga)	RCV000725402	SCV000336698	uncertain significance	not provided	2015-10-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553174	SCV000659572	uncertain significance	Cerebral creatine deficiency syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 217 of the GAMT protein (p.Pro217Leu). This variant is present in population databases (rs139890971, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 205592). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAMT protein function. 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.
Natera, Inc.	RCV001833116	SCV002087003	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2020-01-25	no assertion criteria provided	clinical testing