chr19-1397369-G-A

Variant names:

• chr19-1397369-G-A
• rs1401966018
• NM_000156.6:c.701C>T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.701C>T variant in GAMT is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 234 (p.Thr234Ile). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001335 (1/74914 alleles) in the African / African American population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.268 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). SpliceAI predicts that the variant will have no impact on splicing. To our knowledge, this variant has not been reported in the published literature. It has been previously noted in ClinVar (ID 544252). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 28, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA402990219/MONDO:0012999/026

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 2.97
• 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: Ambry Genetics, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000156.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.701C>T	p.Thr234Ile	missense	Exon 6 of 6	NP_000147.1	Q14353-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.701C>T	p.Thr234Ile	missense	Exon 6 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.971C>T	p.Thr324Ile	missense	Exon 6 of 6	ENSP00000572533.1
	GAMT	ENST00000902472.1		c.704C>T	p.Thr235Ile	missense	Exon 6 of 6	ENSP00000572531.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Cerebral creatine deficiency syndrome (1)
-	1	-	Deficiency of guanidinoacetate methyltransferase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.85
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.31	N
PhyloP100		3.0
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.27
Sift	Benign	0.79	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.035
MutPred		0.15		Loss of glycosylation at T234 (P = 0.0501)
MVP		0.66
ClinPred		0.40	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
Mutation Taster		=66/34	polymorphism

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: rs1401966018; hg19: chr19-1397368;