19-1398994-GC-GCC

Position:

• chr19-1398994-GC-GCC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2_Supporting PVS1_Strong PM3_Supporting PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.491dup (p.Val165ArgfsTer26) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong; PMID:11136556). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 in the East Asian population, which is less than the ClinGen CCDS VCEP's threshold (<0.0004) (PM2_Supporting). The variant was found in homozygosity in one patient who meets the ClinGen CCDS VCEP's PP4 specifications (PMID 12557293). This variant was also found in compound heterozygosity in two patients who meet ClinGen CCDS VCEP’s PP4 specifications; one with the variant c.564G>T (p. Met188Ile) (PMID 28438604) or "IVS5-3C>G" (PMID 11136556). However, the in trans data from these two patients will be used in the assessment of the second variant and is not included here to avoid circular logic. (PM3_Supporting). Three patients have been reported with this variant and clinical and biochemical features consistent with GAMT deficiency including an adult patient with low creatine and elevated GAA in urine, plasma, and CSF, <10% normal GAMT activity in fibroblasts, and absent creatine peak with GAA detected on MRS (PMID 12557293), low creatine and elevated GAA in plasma and urine and absent creatine peak on MRS (PMID 28438604), and elevated GAA in plasma, urine, and CSF, and lacking creatine peak on brain MRS (PMID 1136556)(PP4_Strong). There is a ClinVar entry for this variant (Variation ID: 495685) 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): PVS1_Strong, PP4_Strong, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA9043628/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: GAMT NM_000156.6 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 5.84

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 Pathogenic. Variant got 10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAMT	NM_000156.6	c.491_492insG	p.Val165ArgfsTer26	frameshift_variant	5/6	ENST00000252288.8
GAMT	NM_138924.3	c.491_492insG	p.Val165ArgfsTer26	frameshift_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8	c.491_492insG	p.Val165ArgfsTer26	frameshift_variant	5/6	1	NM_000156.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250692 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135780

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461116 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 726862

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 07, 2020	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_000156.6:c.491dup (p.Val165ArgfsTer26) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong; PMID: 11136556). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 in the East Asian population, which is less than the ClinGen CCDS VCEP's threshold (<0.0004) (PM2_Supporting). The variant was found in homozygosity in one patient who meets the ClinGen CCDS VCEP's PP4 specifications (PMID 12557293). This variant was also found in compound heterozygosity in two patients who meet ClinGen CCDS VCEP’s PP4 specifications; one with the variant c.564G>T (p. Met188Ile) (PMID 28438604) or "IVS5-3C>G" (PMID 11136556). However, the in trans data from these two patients will be used in the assessment of the second variant and is not included here to avoid circular logic. (PM3_Supporting). Three patients have been reported with this variant and clinical and biochemical features consistent with GAMT deficiency including an adult patient with low creatine and elevated GAA in urine, plasma, and CSF, <10% normal GAMT activity in fibroblasts, and absent creatine peak with GAA detected on MRS (PMID 12557293), low creatine and elevated GAA in plasma and urine and absent creatine peak on MRS (PMID 28438604), and elevated GAA in plasma, urine, and CSF, and lacking creatine peak on brain MRS (PMID 1136556)(PP4_Strong). There is a ClinVar entry for this variant (Variation ID: 495685) 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): PVS1_Strong, PP4_Strong, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2017	Variant summary: The GAMT c.491dupG (p.Val165Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent GAMT protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/120398 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAMT variant (0.001118). This variant has been reported in GAMTD patients both as homozygote and compound heterozygote. In addition, the GAMT activity in lymphoblasts was less than 10% of lower limit of controls (schulze_AN_2003). Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 17, 2022	ACMG classification criteria: PVS1 very strong, PS4 moderated, PM2 moderated, PM3 moderated -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 20, 2024	- -

Cerebral creatine deficiency syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	This sequence change creates a premature translational stop signal (p.Val165Argfs*26) in the GAMT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 72 amino acid(s) of the GAMT protein. This variant is present in population databases (rs768985121, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with cerebral creatine deficiency syndrome (PMID: 11136556, 12557293, 28438604). ClinVar contains an entry for this variant (Variation ID: 495685). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 02, 2021	The p.Val165fs variant in GAMT has been reported in 3 individuals with cerebral creatine deficiency syndrome (PMID: 11136556, 12557293, 28438604), and has been identified in in 0.01% (2/19944) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs768985121). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 3 affected individuals, 1 of those was a homozygote and 2 were compound heterozygotes that carried variants of uncertain significance in trans, which increases the likelihood that the p.Val165fs variant is pathogenic (Variation ID: 939221; PMID: 11136556, 12557293, 28438604). This variant has also been reported in ClinVar (Variation ID#: 495685) and has been interpreted as pathogenic by Integrated Genetics (Laboratory Corporation of America) and Invitae. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 165 and leads to a premature termination codon 26 amino acids downstream. This termination codon occurs within the terminal 50 bases of the penultimate exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GAMT gene is an established disease mechanism in autosomal recessive cerebral creatine deficiency syndrome. The phenotype of individuals homozygous or compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 11136556, 12557293, 28438604). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PVS1_strong, PM3, PP4_strong, PM2_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs749390953; hg19: chr19-1398993;