rs121909272

Variant names:

• chr19-1398980-C-T
• rs121909272
• NM_000156.6:c.506G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3_Supporting PP4_Strong PM3 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.505T>A variant in GAMT is a missense variant predicted to cause substitution of a cysteine by tyrosine at amino acid 169 (p.Cys169Tyr). This variant has been detected in 4 unrelated individuals with GAMT deficiency (PMID:15651030, PMID:24415674, PMID:24268530, PMID:24268530). These individuals were homozygous for the variant (1pt, PM3) (PMID:15651030, PMID:24415674, PMID:24268530, PMID:24268530). One of the individuals reported showed deficient (<5% wild-type) GAMT activity in lymphoblasts and elevated GAA in plasma and elevated GAA in urine (PMID:15651030); one individual showed absent creatine peak on brain MRS and elevated urine GAA (PMID:24415674); and one individual showed absent creatine peak on brain MRS (PMID:32606525) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (2/34566 alleles) in the Latino/Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in GAMT-deficient fibroblasts resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID:24415674)(PS3_Supporting). The computational predictor REVEL gives a score of 0.754 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 8304, 2 star review status) with 2 submitters classifying the variant as pathogenic and 3 submitters classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PM3, PP3, PP4_Strong.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA254379/MONDO:0012999/026

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 5.84
• Publications: 6 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: Likely_pathogenic. The variant received 9 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.506G>A	p.Cys169Tyr	missense	Exon 5 of 6	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.506G>A	p.Cys169Tyr	missense	Exon 5 of 5	NP_620279.1	Q14353-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.506G>A	p.Cys169Tyr	missense	Exon 5 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.776G>A	p.Cys259Tyr	missense	Exon 5 of 6	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.506G>A	p.Cys169Tyr	missense	Exon 5 of 5	ENSP00000403536.2	Q14353-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250898 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461162 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726868

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52734

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Deficiency of guanidinoacetate methyltransferase (7)
2	-	-	Cerebral creatine deficiency syndrome (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.092	D
MutationAssessor	Benign	1.5	L
PhyloP100		5.8
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.88		Loss of stability (P = 0.1633)
MVP		0.92
MPC		0.83
ClinPred		0.78	D
GERP RS		4.0
Varity_R		0.85
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs121909272; hg19: chr19-1398979;