rs776498025

Positions:

• chr19-1401455-G-T

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 1P and 2B. PM2_Supporting BS3_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.22C>A variant in GAMT is a missense variant that is predicted to result in the substitution of proline by threonine at amino acid 8 (p.Pro8Thr). One patient, who is heterozygous for the variant, has been reported. This individual, who presented with severe global develpomental delay, hypotonia, and intractable seizures, died at 11 months of age. Urine and plasma guanidinoacetate were elevated 2.5 and 1.8 times, respectively. However, on 1H-MRS, creatine peak was about 90% of normal, marginally low, which was not suggestive of GAMT deficiency(PMID:24415674) (PP4 not applied). GAA-deficient fibroblasts overexpressing the c.22C>A (p.Pro8Thr) variant showed similar GAMT enzyme activity as those transfected with wild-type cDNA (PMID:24415674) (BS3_Supporting). The computational predictor REVEL gives a score of 0.479 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00023 (7/30820 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 205598). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): BS3_Supporting, BP4, PM2_Supporting. Although this variant meets criteria for a classification of Variant of Uncertain Significance, the ClinGen Cerebral Creatine Deficiencies VCEP considers this variant suspicious for Likely Benign. Future literature may warrant a reclassification of this variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA314840/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:6 B:1
• Conservation: PhyloP100: 7.17

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 Uncertain_significance. Variant got -1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.22C>A	p.Pro8Thr	missense_variant	1/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.22C>A	p.Pro8Thr	missense_variant	1/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.22C>A	p.Pro8Thr	missense_variant	1/6	1	NM_000156.6	ENSP00000252288	P1
GAMT	ENST00000447102.8	c.22C>A	p.Pro8Thr	missense_variant	1/5	2		ENSP00000403536
GAMT	ENST00000640762.1	c.22C>A	p.Pro8Thr	missense_variant	1/6	5		ENSP00000492031

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000945

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000144 AC: 6 AN: 41720 Hom.: 0 AF XY: 0.000161 AC XY: 4 AN XY: 24886

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 SAS exome AF: 0.000107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000323

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000177 AC: 219 AN: 1239768 Hom.: 1 Cov.: 31 AF XY: 0.000165 AC XY: 100 AN XY: 605594

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000217

Gnomad4 ASJ exome AF: 0.0000498

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000679

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.000256

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74382

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000457 AC: 2

Asia WGS AF: 0.000290 AC: 1 AN: 3466

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Feb 23, 2023	The NM_000156.6:c.22C>A variant in GAMT is a missense variant that is predicted to result in the substitution of proline by threonine at amino acid 8 (p.Pro8Thr). One patient, who is heterozygous for the variant, has been reported. This individual, who presented with severe global develpomental delay, hypotonia, and intractable seizures, died at 11 months of age. Urine and plasma guanidinoacetate were elevated 2.5 and 1.8 times, respectively. However, on 1H-MRS, creatine peak was about 90% of normal, marginally low, which was not suggestive of GAMT deficiency(PMID: 24415674) (PP4 not applied). GAA-deficient fibroblasts overexpressing the c.22C>A (p.Pro8Thr) variant showed similar GAMT enzyme activity as those transfected with wild-type cDNA (PMID: 24415674) (BS3_Supporting). The computational predictor REVEL gives a score of 0.479 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00023 (7/30820 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 205598). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): BS3_Supporting, BP4, PM2_Supporting. Although this variant meets criteria for a classification of Variant of Uncertain Significance, the ClinGen Cerebral Creatine Deficiencies VCEP considers this variant suspicious for Likely Benign. Future literature may warrant a reclassification of this variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 13, 2020	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2017

The p.P8T variant (also known as c.22C>A), located in coding exon 1 of the GAMT gene, results from a C to A substitution at nucleotide position 22. The proline at codon 8 is replaced by threonine, an amino acid with highly similar properties. This alteration was found to be heterozygous in one individual with no identifiable second alteration in the GAMT gene who presented with severe global developmental delay, hypotonia, and intractable epilepsy of unknown etiology; however, the individual’s MRS imaging was not consistent with guanidinoacetate methyltransferase deficiency (GAMT-D) (Mercimek-Mahmutoglu S et al. Hum. Mutat., 2014 Apr; 35:462-9; Desroches CL et al. Mol. Genet. Genomics, 2015 Dec; 290:2163-71). In addition, functional studies suggested that the alteration did not impact GAMT enzyme activity (Mercimek-Mahmutoglu S et al. Hum. Mutat., 2014 Apr; 35:462-9; Desroches CL et al. Mol. Genet. Genomics, 2015 Dec; 290:2163-71). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cerebral creatine deficiency syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 8 of the GAMT protein (p.Pro8Thr). This variant is present in population databases (rs776498025, gnomAD 0.02%). This missense change has been observed in individual(s) with severe GDD, hypotonia, intractable epilepsy (PMID: 24415674). ClinVar contains an entry for this variant (Variation ID: 205598). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAMT protein function. Experimental studies have shown that this missense change does not substantially affect GAMT function (PMID: 24415674). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2020

This variant is associated with the following publications: (PMID: 26003046, 24415674) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Benign	0.010
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.5	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N;.;N
REVEL	Uncertain	0.48
Sift	Benign	0.040	D;.;D
Sift4G	Uncertain	0.0090	D;.;D
Polyphen		0.041	B;.;.
Vest4		0.42
MVP		0.95
MPC		0.55
ClinPred		0.30	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.87

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: rs776498025; hg19: chr19-1401454;