rs17851582

Variant names:

• chr19-1397444-G-A
• rs17851582
• NM_000156.6:c.626C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-1397444-G-A
• chr19-1397444-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.626C>T variant in GAMT is a missense variant predicted to result in the substitution of threonine for methionine at amino acid 209 (p.Thr209Met). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.09656 (12354/ 127944 alleles) in the European non-Finnish population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). There are 987 homozygotes in gnomAD v2.1.1. Given that GAMT deficiency has an early onset, this data supports that the variant does not cause the condition (BS2). The computational predictor REVEL gives a score of 0.313 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). It has been previously reported in a large Italian family (PMID:12468279), where it did not segregate with AGAT deficiency, including being found in the homozygous state in the father, who was asymptomatic and had normal GAMT enzyme activity. It has also been found in presumed cis with the c.160G>C (p.Ala54Pro) variant in a patient with severe GAMT deficiency, as both parents were heterozygous for both the c.160G>C variant and c.626C>T variant and the patient was homozygous for both variants (PMID:15108290). In this publication (PMID:15108290), the c.626C>T was classified as a benign polymorphism due to its high frequency in a group of control individuals screened. It is noted in ClinVar (Variation ID: 21068). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): BA1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA288884/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.069 (479 hom., cov: 33)
  • Exomes 𝑓: 0.096 (7395 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Benign reviewed by expert panel B:16 O:1
• Conservation: PhyloP100: 2.84
• Publications: 24 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: Benign. The variant received -13 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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 rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.626C>T	p.Thr209Met	missense_variant	Exon 6 of 6	ENST00000252288.8	NP_000147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.626C>T	p.Thr209Met	missense_variant	Exon 6 of 6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000640762.1	c.557C>T	p.Thr186Met	missense_variant	Exon 6 of 6	5		ENSP00000492031.1
GAMT	ENST00000640164.1	n.459C>T		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10583 AN: 152176 Hom.: 479 Cov.: 33

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0618

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.000768

Gnomad SAS AF: 0.0656

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0670

GnomAD2 exomes AF: 0.0763 AC: 18891 AN: 247438 AF XY: 0.0774

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0784

Gnomad ASJ exome AF: 0.0651

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.0951

Gnomad OTH exome AF: 0.0840

GnomAD4 exome AF: 0.0962 AC: 140321 AN: 1458180 Hom.: 7395 Cov.: 32 AF XY: 0.0958 AC XY: 69495 AN XY: 725482

African (AFR) AF: 0.0140 AC: 470 AN: 33476

American (AMR) AF: 0.0762 AC: 3408 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0679 AC: 1774 AN: 26124

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39694

South Asian (SAS) AF: 0.0693 AC: 5979 AN: 86258

European-Finnish (FIN) AF: 0.104 AC: 5210 AN: 49912

Middle Eastern (MID) AF: 0.0395 AC: 228 AN: 5768

European-Non Finnish (NFE) AF: 0.106 AC: 117763 AN: 1111880

Other (OTH) AF: 0.0907 AC: 5472 AN: 60356

GnomAD4 genome AF: 0.0695 AC: 10579 AN: 152294 Hom.: 479 Cov.: 33 AF XY: 0.0674 AC XY: 5018 AN XY: 74468

African (AFR) AF: 0.0179 AC: 744 AN: 41564

American (AMR) AF: 0.0617 AC: 944 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0602 AC: 209 AN: 3472

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5194

South Asian (SAS) AF: 0.0657 AC: 317 AN: 4828

European-Finnish (FIN) AF: 0.102 AC: 1080 AN: 10626

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7068 AN: 67992

Other (OTH) AF: 0.0663 AC: 140 AN: 2112

Alfa AF: 0.0861 Hom.: 956

Bravo AF: 0.0640

TwinsUK AF: 0.0984 AC: 365

ALSPAC AF: 0.106 AC: 410

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.0972 AC: 836

ExAC AF: 0.0746 AC: 9036

Asia WGS AF: 0.0260 AC: 92 AN: 3478

EpiCase AF: 0.0913

EpiControl AF: 0.0865

ClinVar

Significance: Benign

Submissions summary: Benign:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Benign:5 Other:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 06, 2022

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000156.6:c.626C>T variant in GAMT is a missense variant predicted to result in the substitution of threonine for methionine at amino acid 209 (p.Thr209Met). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.09656 (12354/ 127944 alleles) in the European non-Finnish population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). There are 987 homozygotes in gnomAD v2.1.1. Given that GAMT deficiency has an early onset, this data supports that the variant does not cause the condition (BS2). The computational predictor REVEL gives a score of 0.313 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). It has been previously reported in a large Italian family (PMID: 12468279), where it did not segregate with AGAT deficiency, including being found in the homozygous state in the father, who was asymptomatic and had normal GAMT enzyme activity. It has also been found in presumed cis with the c.160G>C (p.Ala54Pro) variant in a patient with severe GAMT deficiency, as both parents were heterozygous for both the c.160G>C variant and c.626C>T variant and the patient was homozygous for both variants (PMID: 15108290). In this publication (PMID: 15108290), the c.626C>T was classified as a benign polymorphism due to its high frequency in a group of control individuals screened. It is noted in ClinVar (Variation ID: 21068). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): BA1, BS2, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

Jun 24, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:5

Nov 09, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAMT c.626C>T (p.Thr209Met) results in a non-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 0.076 in 273748 control chromosomes in the gnomAD database, including 972 homozygotes. The observed variant frequency is approximately 70 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAMT causing Guanidinoactetate methyltransferase deficiency phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.626C>T in individuals affected with Guanidinoactetate methyltransferase deficiency has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Battini 2002). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as benign (1x)/likely benign(1x). Based on the evidence outlined above, the variant was classified as likely benign. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 19. Only high quality variants are reported. -

May 28, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Leigh syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial complex I deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Feb 10, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.8	M;.
PhyloP100		2.8
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.31
Sift	Benign	0.19	T;.
Sift4G	Uncertain	0.036	D;.
Polyphen		1.0	D;.
Vest4		0.056
ClinPred		0.025	T
GERP RS		5.1
Varity_R		0.20
Mutation Taster		=87/13	polymorphism (auto)

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: rs17851582; hg19: chr19-1397443; COSMIC: COSV52041101; COSMIC: COSV52041101;