chr19-1399184-C-A

Position:

• chr19-1399184-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PM5 PP4_Strong PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.403G>T (p.Asp135Tyr) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID:19027335). This variant was identified in 0.001470% (1/68032) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD) (PM2_Supporting). The patient previously reported was a reported compound heterozygote that carried a pathogenic variant, c.507_521dup15 (p.C169_S173dup; ClinVar Variation ID: 431959), in unknown phase (PM3_Supporting). This individual showed reduced creatine peak on brain magnetic resonance spectroscopy and elevated plasma GAA with low creatine with full GAMT gene sequencing (PP4_Strong). The p.Asp135Tyr variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.938) (PP3). A different missense variant at the same amino acid residue, p.Asp135Asn, has been previously reported pathogenic (ClinVar Variation ID: 573140) (PM5). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP Criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PM2_Supporting, PM3_Supporting, PM5, PP3, PP4_Strong (Richards 2015).(Classification approved by the ClinGen CCDS VCEP on March 23, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA402995388/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 6.05

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6	c.403G>T	p.Asp135Tyr	missense_variant	4/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.403G>T	p.Asp135Tyr	missense_variant	4/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.403G>T	p.Asp135Tyr	missense_variant	4/6	1	NM_000156.6	ENSP00000252288	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461284 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 13, 2023	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Mar 23, 2023	The NM_000156.6:c.403G>T (p.Asp135Tyr) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID: 19027335). This variant was identified in 0.001470% (1/68032) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD) (PM2_Supporting). The patient previously reported was a reported compound heterozygote that carried a pathogenic variant, c.507_521dup15 (p.C169_S173dup; ClinVar Variation ID: 431959), in unknown phase (PM3_Supporting). This individual showed reduced creatine peak on brain magnetic resonance spectroscopy and elevated plasma GAA with low creatine with full GAMT gene sequencing (PP4_Strong). The p.Asp135Tyr variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.938) (PP3). A different missense variant at the same amino acid residue, p.Asp135Asn, has been previously reported pathogenic (ClinVar Variation ID: 573140) (PM5). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP Criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PM2_Supporting, PM3_Supporting, PM5, PP3, PP4_Strong (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.9	D;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.99
MutPred		0.89		Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);
MVP		0.99
MPC		0.71
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs774144200; hg19: chr19-1399183;