15-45368137-T-G

Variant names:

• chr15-45368137-T-G
• rs397514709
• NM_001482.3:c.608A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP4_Strong PM2_Supporting PS3_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.608A>C variant in GATM is a missense variant that is predicted to result in substitution of tyrosine by serine at amino acid 203 (p.Tyr203Ser). This variant has been previously reported in two siblings (PMID:23770102), both of whom showed significantly decreased creatine peak on H1-MRS and low GAA in plasma and low creatine in plasma (PP4_Strong). Both siblings were homozygous for the variant and their parents, who were first cousins, were confirmed to be heterozygous (PM3_Supporting). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). When expressed in HeLa cells, the variant had 0% of wild-type GATM activity (PMID:27233232) (PS3_Supporting). The computational predictor REVEL gives a score of 0.64 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on AGAT function. SpliceAI predicts that the variant has no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 55921). In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PP4_Strong, PS3_Supporting, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA263244/MONDO:0012996/025

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATM NM_001482.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.58
• Publications: 5 publications found

Genes affected

GATM (HGNC:4175): (glycine amidinotransferase) This gene encodes a mitochondrial enzyme that belongs to the amidinotransferase family. This enzyme is involved in creatine biosynthesis, whereby it catalyzes the transfer of a guanido group from L-arginine to glycine, resulting in guanidinoacetic acid, the immediate precursor of creatine. Mutations in this gene cause arginine:glycine amidinotransferase deficiency, an inborn error of creatine synthesis characterized by cognitive disability, language impairment, and behavioral disorders. [provided by RefSeq, Jul 2008]

GATM Gene-Disease associations (from GenCC):

• AGAT deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, G2P
• Fanconi renotubular syndrome 1

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• primary Fanconi syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATM	NM_001482.3	c.608A>C	p.Tyr203Ser	missense_variant	Exon 4 of 9	ENST00000396659.8	NP_001473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8	c.608A>C	p.Tyr203Ser	missense_variant	Exon 4 of 9	1	NM_001482.3	ENSP00000379895.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency Pathogenic:2

Aug 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 11, 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_001482.3:c.608A>C variant in GATM is a missense variant that is predicted to result in substitution of tyrosine by serine at amino acid 203 (p.Tyr203Ser). This variant has been previously reported in two siblings (PMID: 23770102), both of whom showed significantly decreased creatine peak on H1-MRS and low GAA in plasma and low creatine in plasma (PP4_Strong). Both siblings were homozygous for the variant and their parents, who were first cousins, were confirmed to be heterozygous (PM3_Supporting). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). When expressed in HeLa cells, the variant had 0% of wild-type GATM activity (PMID: 27233232) (PS3_Supporting). The computational predictor REVEL gives a score of 0.64 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on AGAT function. SpliceAI predicts that the variant has no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 55921). In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PP4_Strong, PS3_Supporting, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on April 11, 2025). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.3	M;M;.
PhyloP100		7.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-9.0	D;D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.76		Gain of disorder (P = 0.0225);Gain of disorder (P = 0.0225);.;
MVP		0.67
MPC		2.1
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.97
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs397514709; hg19: chr15-45660335;