Submissions for variant NM_000156.6(GAMT):c.328G>T (p.Val110Phe)

gnomAD frequency: 0.00002  dbSNP: rs753198836

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV002305455	SCV002600152	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2022-06-06	reviewed by expert panel	curation	The NM_000156.6:c.328G>T variant in GAMT is a missense variant predicted to cause substitution of valine by phenylalanine at amino acid 110 (p.Val110Phe). The variant was found in compound heterozygosity, phase unknown, with a pathogenic variant in GAMT (c.327G>A) in one patient with elevated guanidinoacetate in urine and a partially absent creatine peak on brain magentic resonance spectroscopy (PMID 24415674) (PP4_Strong, PM3_Supporting). Expression of the variant in fibroblasts resulted in no detectable fusion protein when the variant was expressed in GAMT-deficient fibroblasts indicating that this variant may impact protein function (PMID 24415674)(PS3_Supporting). The computational predictor REVEL gives a score of 0.928 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). This variant is absent in gnomAD v.2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 205580. In summary, this variant meets the criteria to be classified as Likely pathogenic 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): PP4_strong, PS3_Supporting, PM3_Supporting, PM2_Supporting, PP3. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
GeneDx	RCV000187565	SCV000241159	likely pathogenic	not provided	2017-02-01	criteria provided, single submitter	clinical testing	p.Val110Phe (GTC>TTC): c.328 G>T in exon 3 of the GAMT gene (NM_000156.4) The c.328 G>T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Multiple in silico algorithms predict that c.328 G>T damages or destroys the natural splice acceptor site in intron 2 and leads to abnormal gene splicing. If c.328 G>T does not alter splicing, it will result in the V110F missense change. The V110F variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the c.328 G>T variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517861	SCV003242074	uncertain significance	Cerebral creatine deficiency syndrome	2022-05-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 110 of the GAMT protein (p.Val110Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with guanidinoacetate methyltransferase deficiency (PMID: 24415674). ClinVar contains an entry for this variant (Variation ID: 205580). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GAMT function (PMID: 24415674). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.