Submissions for variant NM_000156.6(GAMT):c.152A>C (p.His51Pro)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV003334076	SCV004042611	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-09-12	reviewed by expert panel	curation	The NM_000156.6:c.152A>C variant in GAMT is a missense variant that is predicted to result in the substitution of histidine by proline at amino acid 51 (p.His51Pro). One proband has been reported with mild developmental delay, anti-epileptic drug responsive seizures, and autistic features, with a normal brain MRI. This individual had elevated guanidinoacetate in urine and, on MRS, creatine peak was partially absent and guanidinoacetate was absent (PMID: 15108290, 24415674) (PP4_Strong). This individual is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.526dupG. The variants were confirmed to be in trans by parental testing (PM3). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). When the variant was expressed in a primary GAMT-deficient human fibroblast cell line, no detectable expression could be seen on Western blot and the GAMT activity was very low (<4%)(PMID 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.814 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): PP4_Strong, PM3, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP, Sept 12, 2023)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003050512	SCV003443803	uncertain significance	Cerebral creatine deficiency syndrome	2022-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 51 of the GAMT protein (p.His51Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GAMT deficiency (PMID: 15108290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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. Experimental studies have shown that this missense change affects GAMT function (PMID: 24415674). 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.