19-1397447-C-G

Variant names:

• chr19-1397447-C-G
• rs767887772
• NM_000156.6:c.623G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000156.6(GAMT):​c.623G>C​(p.Arg208Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 0.126
• Publications: 0 publications found

Genes affected

GAMT (HGNC:4136): (guanidinoacetate N-methyltransferase) The protein encoded by this gene is a methyltransferase that converts guanidoacetate to creatine, using S-adenosylmethionine as the methyl donor. Defects in this gene have been implicated in neurologic syndromes and muscular hypotonia, probably due to creatine deficiency and accumulation of guanidinoacetate in the brain of affected individuals. Two transcript variants encoding different isoforms have been described for this gene. Pseudogenes of this gene are found on chromosomes 2 and 13. [provided by RefSeq, Feb 2012]

GAMT Gene-Disease associations (from GenCC):

• guanidinoacetate methyltransferase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1397447-C-G is Pathogenic according to our data. Variant chr19-1397447-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3775038.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.623G>C	p.Arg208Pro	missense_variant	Exon 6 of 6	ENST00000252288.8	NP_000147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.623G>C	p.Arg208Pro	missense_variant	Exon 6 of 6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000640762.1	c.554G>C	p.Arg185Pro	missense_variant	Exon 6 of 6	5		ENSP00000492031.1
GAMT	ENST00000640164.1	n.456G>C		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Pathogenic:1

Mar 18, 2025

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000156.6:c.623G>C variant in GAMT is a missense variant predicted to cause substitution of arginine by proline at amino acid 208 (p.Arg208Pro). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). It has been reported in homozygosity in one individual with clinical symptoms consistent with GAMT deficiency (severe intellectual impairment, intractable seizures, movement disorder), deficienct GAMT activity, and reduction of creatine on brain MRS, who showed clinical improvement on dietary treatment (PMID 24415674, 29506905) (PM3_Supporting, PP4_Strong). When expressed in GAMT-deficient fibroblasts, the variant resulted in ~4% wild type GAMT activity (PMID 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.751, which is in the range (0.644-0.773) that predicts impact to GAMT function at the supporting level (Pejaver et al, 2022, PMID: 36413997) (PP3). Two additional missense variants at this amino acid position have been reported; c.623G>A (p.Arg208His) (ClinVarID: 577478), and c.622C>T (p.Arg208Cys) (ClinVar ID: 544261). Both of these variants have been classified as variants of uncertain significance by the ClinGen CCDS VCEP. There is no ClinVar entry for this variant. 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 CCDS VCEP (Specifications Version 2.0.0): PP4_Strong, PP3, PS3_Supporting, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.3
DANN	Benign	0.76
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.63	T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.3	L;.
PhyloP100		0.13
PROVEAN	Benign	-0.86	N;.
REVEL	Pathogenic	0.75
Sift	Benign	0.21	T;.
Sift4G	Benign	0.067	T;.
Polyphen		0.65	P;.
Vest4		0.11
MutPred		0.44		Gain of glycosylation at T209 (P = 0.0258);.;
MVP		0.48
ClinPred		0.42	T
GERP RS		-5.0
Varity_R		0.60
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs767887772; hg19: chr19-1397446;