chr19-1399149-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got -2 ACMG points: 1P and 3B. PM2_SupportingBP2BP4BP7

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.438A>G (p.Thr146=) variant in GAMT is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -4.7) (BP4, BP7). This variant has been previously reported in an individual with GAMT deficiency who had significantly decreased creatine peak on MRS (PMID:7808840) and GAMT activity <0.1% versus normal in fibroblasts (PMID:11978605). Familial analysis showed that this individual harbored the variant in cis with NM_000156.6:c.299_311dup, (ClinVar Variation ID: 8302; pathogenic based on classification by the ClinGen CCDS VCEP) and had co-inherited these variants from his unaffected mother (BP2); he harbored these variants in trans with the pathogenic variant c.327G>A (ClinVar ID: 21065), inherited from his father. Of note, his unaffected brother was heterozygous for the two maternally co-inherited (c.438A>G and c.299_311dup) variants. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003333 (2/60006 alleles) in the Admixed American, 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: 21066). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. Although the evidence is tending likely benign, the lack of data regarding the impact of this variant on it's own, in the ansence of the other two variants, led to a VUS classification based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP2, BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA341572/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

GAMT
NM_000156.6 synonymous

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:1O:1

Conservation

PhyloP100: -4.24

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -2 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

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 link	c.438A>G	p.Thr146Thr	synonymous_variant	Exon 4 of 6	ENST00000252288.8	NP_000147.1	Q14353-1V9HWB2
GAMT	NM_138924.3 link	c.438A>G	p.Thr146Thr	synonymous_variant	Exon 4 of 5		NP_620279.1	Q14353-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8 link	c.438A>G	p.Thr146Thr	synonymous_variant	Exon 4 of 6	1	NM_000156.6	ENSP00000252288.1		Q14353-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251204

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461480

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase

Uncertain:2Other:1

Aug 14, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 13, 2025

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.438A>G (p.Thr146=) variant in GAMT is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -4.7) (BP4, BP7). This variant has been previously reported in an individual with GAMT deficiency who had significantly decreased creatine peak on MRS (PMID: 7808840) and GAMT activity <0.1% versus normal in fibroblasts (PMID: 11978605). Familial analysis showed that this individual harbored the variant in cis with NM_000156.6:c.299_311dup, (ClinVar Variation ID: 8302; pathogenic based on classification by the ClinGen CCDS VCEP) and had co-inherited these variants from his unaffected mother (BP2); he harbored these variants in trans with the pathogenic variant c.327G>A (ClinVar ID: 21065), inherited from his father. Of note, his unaffected brother was heterozygous for the two maternally co-inherited (c.438A>G and c.299_311dup) variants. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003333 (2/60006 alleles) in the Admixed American, 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: 21066). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. Although the evidence is tending likely benign, the lack of data regarding the impact of this variant on it's own, in the ansence of the other two variants, led to a VUS classification based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP2, BP4, BP7. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025) -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Cerebral creatine deficiency syndrome

Benign:1

Jun 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.67

DANN

Benign

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over