15-45362112-G-C

Variant names:

• chr15-45362112-G-C
• rs1566838768
• NM_001482.3:c.1269C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. BP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001482.3: c.1269C>G variant in GATM is a missense variant predicted to cause substitution of aspartate by glutamate at amino acid 423 (p.Asp423Glu). To our knowledge, this variant has not been reported in the literature in an individual with features of AGAT deficiency. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.092 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function, and SpliceAI does not predict any impact in splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 58991). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA392254551/MONDO:0012996/025

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATM NM_001482.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 3.53
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.1269C>G	p.Asp423Glu	missense_variant	Exon 9 of 9	ENST00000396659.8	NP_001473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8	c.1269C>G	p.Asp423Glu	missense_variant	Exon 9 of 9	1	NM_001482.3	ENSP00000379895.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 12, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D423E variant (also known as c.1269C>G), located in coding exon 9 of the GATM gene, results from a C to G substitution at nucleotide position 1269. The aspartic acid at codon 423 is replaced by glutamic acid, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6496 samples (12992 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Arginine:glycine amidinotransferase deficiency Uncertain:1

Apr 11, 2025

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001482.3: c.1269C>G variant in GATM is a missense variant predicted to cause substitution of aspartate by glutamate at amino acid 423 (p.Asp423Glu). To our knowledge, this variant has not been reported in the literature in an individual with features of AGAT deficiency. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.092 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function, and SpliceAI does not predict any impact in splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 58991). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on April 11, 2025). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.012
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.092
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.021	D
Polyphen		0.0	B
Vest4		0.083
MutPred		0.25		Gain of helix (P = 0.0425);
MVP		0.40
MPC		0.84
ClinPred		0.83	D
GERP RS		3.6
Varity_R		0.22
gMVP		0.67

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: rs1566838768; hg19: chr15-45654310;