rs778279369

Variant names:

• chr19-1397448-G-A
• rs778279369
• NM_000156.6:c.622C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-1397448-G-A
• chr19-1397448-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM5_Supporting PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.622C>T variant in GAMT is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 208 (p.Arg208Cys). The highest continental population minor allele frequency in gnomAD v4.1.0. is 0.00003294 (3/91086 alleles) in the South Asian 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 0.131 which is below the threshold of 0.29, evidence that correlates with no impact to GAMT function (BP4). SpliceAI predicts that the variant has no impact on splicing. Two additional missense variants at this amino acid position have been reported; c.623G>A (p.Arg208His) (ClinVarID: 577478) and c.623G>C (p.Arg208Pro) (PMID 24415674). The ClinGen CCDS VCEP has classified p.Arg208Pro as likely pathogenic, while p.Arg208His has been classified as a VUS (PM5_Supporting). To our knowledge, c.622C>T (p.Arg208Pro) has not been previously reported in the published literature, but has been noted in ClinVar (Variation ID: 544261). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0: PM2_Supporting, PM5_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 28, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA9043556/MONDO:0012999/026

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 0.436
• Publications: 1 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 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.622C>T	p.Arg208Cys	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.622C>T	p.Arg208Cys	missense	Exon 6 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.892C>T	p.Arg298Cys	missense	Exon 6 of 6	ENSP00000572533.1
	GAMT	ENST00000902472.1		c.625C>T	p.Arg209Cys	missense	Exon 6 of 6	ENSP00000572531.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000283 AC: 7 AN: 247330 AF XY: 0.0000372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1457980 Hom.: 0 Cov.: 31 AF XY: 0.0000221 AC XY: 16 AN XY: 725404

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111884

Other (OTH) AF: 0.0000828 AC: 5 AN: 60358

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	-	Deficiency of guanidinoacetate methyltransferase (3)
-	1	-	Cerebral creatine deficiency syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.44
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.13
Sift	Benign	0.10	T
Sift4G	Uncertain	0.045	D
Polyphen		0.0060	B
Vest4		0.062
MutPred		0.42		Loss of disorder (P = 0.1136)
MVP		0.61
ClinPred		0.022	T
GERP RS		0.17
Varity_R		0.21
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778279369; hg19: chr19-1397447;