19-1401418-C-G

Variant names:

• chr19-1401418-C-G
• rs80338734
• NM_000156.6:c.59G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3_Supporting PP4_Strong PP3 PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.59G>C variant in GAMT is a missense variant predicted to cause substitution of tryptophan by serine at amino acid 20 (p.Trp20Ser). This variant has been detected in at least 9 unrelated individuals with GAMT deficiency (PMID:15651030, PMID:16855203, PMID:15108290). Of those individuals, one was compound heterozygous for the variant and a pathogenic variant, c.521G>A (p.Trp174*, in trans (PMID:16855203) and eight individuals were homozygous for the variant (PMID:15651030, PMID:16855203, PMID:15108290) (2 points total) (PM3_Strong). These individuals showed elevated plasma GAA and urine GAA (PMID:15651030, PMID:16855203, PMID:15108290), three also showed deficient (<5% wild-type) GAMT enzyme activity in lymphoblasts (PMID:15651030), and one also showed deficient (<5% wild-type) GAMT enzyme activity in fibroblasts and reduced creatine signal on brain MRS (PMID:16855203, PMID:21140503) (PP4_Strong). Expression of the variant in HeLa cells resulted in 3% wild type GAMT activity indicating that this variant may impact protein function (PMID:17336114)(PS3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 (3/27420 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004); however, as this variant is covered in <50% of individuals in gnomAD v2.1.1, allele frequency estimates may not be reliable and thus PM2_Supporting is not met. The computational predictor REVEL gives a score of 0.94 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: 8303, 2 star review status) with 9 submitters classifying the variant as pathogenic and 1 submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as 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, PM3_Strong, 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/CA340769/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:15 O:2
• Conservation: PhyloP100: 7.44
• Publications: 13 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: Pathogenic. The variant received 10 ACMG points.

• PS3: 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.59G>C	p.Trp20Ser	missense	Exon 1 of 6	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.59G>C	p.Trp20Ser	missense	Exon 1 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.59G>C	p.Trp20Ser	missense	Exon 1 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.59G>C	p.Trp20Ser	missense	Exon 1 of 6	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.59G>C	p.Trp20Ser	missense	Exon 1 of 5	ENSP00000403536.2	Q14353-2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000537 AC: 4 AN: 74462 AF XY: 0.0000928

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000332 AC: 43 AN: 1296552 Hom.: 0 Cov.: 31 AF XY: 0.0000313 AC XY: 20 AN XY: 638052

African (AFR) AF: 0.00 AC: 0 AN: 26520

American (AMR) AF: 0.0000399 AC: 1 AN: 25048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22834

East Asian (EAS) AF: 0.00 AC: 0 AN: 28182

South Asian (SAS) AF: 0.0000579 AC: 4 AN: 69034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32486

Middle Eastern (MID) AF: 0.000246 AC: 1 AN: 4068

European-Non Finnish (NFE) AF: 0.0000329 AC: 34 AN: 1034812

Other (OTH) AF: 0.0000560 AC: 3 AN: 53568

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.000524 AC: 8 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000465 AC: 4

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Deficiency of guanidinoacetate methyltransferase (11)
2	-	-	Cerebral creatine deficiency syndrome (2)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.81		Gain of glycosylation at W20 (P = 2e-04)
MVP		0.98
MPC		0.79
ClinPred		0.93	D
GERP RS		4.0
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.88
Mutation Taster		=18/82	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: rs80338734; hg19: chr19-1401417;