Submissions for variant NM_000156.6(GAMT):c.506G>A (p.Cys169Tyr)

gnomAD frequency: 0.00002  dbSNP: rs121909272

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV000008802	SCV004009598	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-05-25	reviewed by expert panel	curation	The NM_000156.6:c.505T>A variant in GAMT is a missense variant predicted to cause substitution of a cysteine by tyrosine at amino acid 169 (p.Cys169Tyr). This variant has been detected in 4 unrelated individuals with GAMT deficiency (PMID: 15651030, PMID: 24415674, PMID: 24268530, PMID: 24268530). These individuals were homozygous for the variant (1pt, PM3) (PMID: 15651030, PMID: 24415674, PMID: 24268530, PMID: 24268530). One of the individuals reported showed deficient (<5% wild-type) GAMT activity in lymphoblasts and elevated GAA in plasma and elevated GAA in urine (PMID: 15651030); one individual showed absent creatine peak on brain MRS and elevated urine GAA (PMID: 24415674); and one individual showed absent creatine peak on brain MRS (PMID: 32606525) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (2/34566 alleles) in the Latino/Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in GAMT-deficient fibroblasts resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674)(PS3_Supporting). The computational predictor REVEL gives a score of 0.754 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 8304, 2 star review status) with 2 submitters classifying the variant as pathogenic and 3 submitters classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PM3, PP3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023)
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000008802	SCV000999808	pathogenic	Deficiency of guanidinoacetate methyltransferase	2018-12-11	criteria provided, single submitter	clinical testing	This variant was identified in composite heterozygosity with another variant in the same gene in a female patient with IDD. The unaffected parents are both carriers of one of the two variants in the same gene, while the affected brother also harbours both variants in composite heterozygosity
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001762039	SCV001999910	likely pathogenic	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.Cys169Tyr variant in GAMT has been reported in 4 individuals with cerebral creatine deficiency syndrome (PMID: 15651030, 24415674, 24268530, 32606525), segregated with disease in 1 affected relative from 1 family (PMID: 32606525), and has been identified in 0.006% (2/34566) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121909272). 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. Of the 4 affected individuals, all of those were homozygotes which increases the likelihood that the p.Cys169Tyr variant is pathogenic (PMID: 15651030, 24415674, 24268530, 32606525). This variant has also been reported in ClinVar (Variation ID#: 8304) and has been interpreted as pathogenic by OMIM and Center of Genomic Medicine (Geneva, University Hospital of Geneva). In vitro functional studies provide some evidence that the p.Cys169Tyr variant may slightly impact protein function (PMID: 24415674). 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. The phenotype of individuals homozygous or compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 24415674, 2426853, 15651030, 32606525). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM3, PM2_supporting, PP3, PS3_supporting, PP4_strong (Richards 2015).
Revvity Omics, Revvity	RCV000008802	SCV002018385	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2021-04-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001762039	SCV002302960	likely pathogenic	Cerebral creatine deficiency syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This variant disrupts the p.Cys169 amino acid residue in GAMT. Other variant(s) that disrupt this residue have been observed in individuals with GAMT-related conditions (PMID: 23660394), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GAMT function (PMID: 24415674). 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. ClinVar contains an entry for this variant (Variation ID: 8304). This missense change has been observed in individual(s) with Cerebral creatine deficiency syndrome (PMID: 15651030, 23234264, 24415674). This variant is present in population databases (rs121909272, gnomAD 0.006%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 169 of the GAMT protein (p.Cys169Tyr). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV000008802	SCV004198565	pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-10-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000008802	SCV005185964	pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-05-03	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.506G>A (p.Cys169Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250898 control chromosomes. c.506G>A has been reported in the literature in at-least two individuals affected with Cerebral Creatine Deficiency Syndrome (example, Caldeira Araujo_2005, Mercimek-Mahmutoglu_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in diminished normal activity in fibroblast cell line (Mercimek-Mahmutoglu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 15651030, 24415674). ClinVar contains an entry for this variant (Variation ID: 8304). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV004700204	SCV005201741	pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate impaired protein expression and GAMT activity (Mercimek-Mahmutoglu et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 23234264, 24268530, 19027335, 24415674, 15651030, 32606525)
OMIM	RCV000008802	SCV000029012	pathogenic	Deficiency of guanidinoacetate methyltransferase	2005-03-01	no assertion criteria provided	literature only