rs200833152

Positions:

• chr19-1401398-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000156.6:c.79T>C variant in GAMT is a missense variant that is predicted to result in the substitution of tyrosine by histidine at amino acid 27 (p.Tyr27His). This variant was identified in the homozygous state in an individual with normal GAMT enzyme activity in fibroblasts (PMID:24415674). The variant is present in gnomAD v2.1.1. at a maximum population frequency of 0.00471 (>0.003, cutoff for BA1) and found in the homozygous state in 2 individuals in gnomAD v2.1.1 (BA1). In fibroblasts, overexpressing the GAMT c.79T>C (p.Tyr27His) variant, restored GAMT activity to similar levels as the wild-type GAMT transfection (PMID:24415674)(BS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 167131). In summary, this variant meets the criteria to be classified as benign 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): BA1, BS3_Supporting.(Classification approved by the ClinGen CCDS VCEP on February 8, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA295620/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (18 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:3 B:13 O:1
• Conservation: PhyloP100: 7.08

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 Benign. Variant got -9 ACMG points.

• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.79T>C	p.Tyr27His	missense_variant	1/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.79T>C	p.Tyr27His	missense_variant	1/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.79T>C	p.Tyr27His	missense_variant	1/6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000447102.8	c.79T>C	p.Tyr27His	missense_variant	1/5	2		ENSP00000403536.2
GAMT	ENST00000640762.1	c.79T>C	p.Tyr27His	missense_variant	1/6	5		ENSP00000492031.1

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 516 AN: 152024 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00282 AC: 245 AN: 86858 Hom.: 1 AF XY: 0.00268 AC XY: 134 AN XY: 49930

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00444

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00456 AC: 5989 AN: 1313380 Hom.: 18 Cov.: 31 AF XY: 0.00438 AC XY: 2834 AN XY: 647264

Gnomad4 AFR exome AF: 0.00130

Gnomad4 AMR exome AF: 0.00455

Gnomad4 ASJ exome AF: 0.000430

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00136

Gnomad4 NFE exome AF: 0.00532

Gnomad4 OTH exome AF: 0.00403

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152132 Hom.: 4 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74374

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00495

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00513 Hom.: 1

Bravo AF: 0.00357

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00123 AC: 5

ESP6500EA AF: 0.00239 AC: 19

ExAC AF: 0.00165 AC: 164

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:3 Benign:13 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 29, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	GAMT: PP3, BS2 -

Deficiency of guanidinoacetate methyltransferase Pathogenic:1 Uncertain:1 Benign:2

Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Feb 08, 2023	NM_000156.6:c.79T>C variant in GAMT is a missense variant that is predicted to result in the substitution of tyrosine by histidine at amino acid 27 (p.Tyr27His). This variant was identified in the homozygous state in an individual with normal GAMT enzyme activity in fibroblasts (PMID: 24415674). The variant is present in gnomAD v2.1.1. at a maximum population frequency of 0.00471 (>0.003, cutoff for BA1) and found in the homozygous state in 2 individuals in gnomAD v2.1.1 (BA1). In fibroblasts, overexpressing the GAMT c.79T>C (p.Tyr27His) variant, restored GAMT activity to similar levels as the wild-type GAMT transfection (PMID: 24415674)(BS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 167131). In summary, this variant meets the criteria to be classified as benign 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): BA1, BS3_Supporting. (Classification approved by the ClinGen CCDS VCEP on February 8, 2023). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 11, 2020	- -

not specified Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2023	Variant summary: GAMT c.79T>C (p.Tyr27His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 86858 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAMT causing Cerebral Creatine Deficiency Syndrome 2 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.79T>C in individuals affected with Cerebral Creatine Deficiency Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=1, VUS n=2, likely benign n=3, benign n=5). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 16, 2014	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cerebral creatine deficiency syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

GAMT-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Guanidinoacetate methyltransferase (GAMT) deficiency Other:1

not provided, no classification provided

phenotyping only

GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies

-

Variant interpreted as Uncertain significance and reported on 08-22-2014 by GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.0093	T;T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.0	M;.;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.5	N;.;N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.52
MVP		0.91
MPC		0.72
ClinPred		0.066	T
GERP RS		3.1
Varity_R		0.62
gMVP		0.80

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: rs200833152; hg19: chr19-1401397;