Submissions for variant NM_000156.6(GAMT):c.317A>C (p.Gln106Pro)

gnomAD frequency: 0.00001  dbSNP: rs145817990

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV003302757	SCV004009595	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2023-05-11	reviewed by expert panel	curation	The NM_000156.6:c.317A>C variant in GAMT is a missense variant that is predicted to result in the substitution of glutamine by proline at amino acid 106 (p.Gln106Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000156 (3/19226 alleles) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). In HeLa cells, expression of the variant resulted in <15% of wild-type GAMT enzyme activity (PMID: 26003046) (PS3_Supporting). The computational predictor REVEL gives a score of 0.75 which meets the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). To our knowledge, this variant has not been reported in an individual with GAMT deficiency in the published literature. There is a ClinVar entry for this variant (Variation ID: 449690). 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 Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 11, 2023)
GeneDx	RCV000519993	SCV000618031	likely pathogenic	not provided	2017-10-19	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the GAMT gene. Functional studies of the Q106P variant demonstrate a significant decrease of GAMT enzyme activity in HeLa cells, thus indicating pathogenicity (Desroches et al., 2015). The Q106P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Q106P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species; and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001764518	SCV001999925	uncertain significance	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.Gln106Pro variant in GAMT has not been previously reported in individuals with cerebral creatine deficiency syndrome but has been identified in 0.02% (3/19226) of African/African-American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs145817990). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 449690) and has been interpreted as likely pathogenic by GeneDx. In vitro functional studies provide some evidence that the p.Gln106Pro variant may slightly impact protein function (PMID: 26003046). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gln106Pro variant is uncertain. ACMG/AMP Criteria applied: PS3_supporting, PP3, PM2_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001764518	SCV004297975	uncertain significance	Cerebral creatine deficiency syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 106 of the GAMT protein (p.Gln106Pro). This variant is present in population databases (rs145817990, gnomAD 0.02%). 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: 449690). 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: 26003046). 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.