rs776498025

Variant names:

• chr19-1401455-G-T
• rs776498025
• NM_000156.6:c.22C>A

Variant summary

Our verdict is Uncertain significance. The variant received -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
• Publications: 3 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received -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 rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.22C>A	p.Pro8Thr	missense_variant	Exon 1 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.22C>A	p.Pro8Thr	missense_variant	Exon 1 of 5		NP_620279.1

Ensembl

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

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

GnomAD2 exomes AF: 0.000144 AC: 6 AN: 41720 AF XY: 0.000161

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: 0.000323

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

African (AFR) AF: 0.00 AC: 0 AN: 25310

American (AMR) AF: 0.000217 AC: 4 AN: 18424

Ashkenazi Jewish (ASJ) AF: 0.0000498 AC: 1 AN: 20084

East Asian (EAS) AF: 0.00 AC: 0 AN: 27432

South Asian (SAS) AF: 0.0000679 AC: 4 AN: 58924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30606

Middle Eastern (MID) AF: 0.00222 AC: 8 AN: 3608

European-Non Finnish (NFE) AF: 0.000188 AC: 189 AN: 1004506

Other (OTH) AF: 0.000256 AC: 13 AN: 50874

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10586

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67952

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

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

Feb 23, 2023

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Jan 13, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 02, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Mar 07, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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&rsquo;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

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 28, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		7.2
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
PromoterAI		0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.87
Mutation Taster		=63/37	polymorphism

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: rs776498025; hg19: chr19-1401454;