19-1399184-C-T

Variant names:

• chr19-1399184-C-T
• rs774144200
• NM_000156.6:c.403G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PS3_Supporting PM5_Supporting PM3 PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000156.6(GAMT):c.403G>A variant in GAMT is predicted to result in the substitution of aspartate by asparagine at amino acid 135 (p.Asp135Asn). Four probands and one affected sibling have been reported with this variant, all with clinical symptoms consistent with GAMT deficiency, evidence of elevated guanidinoacetate and low creatine in plasma and/or urine, and reduced creatine on brain MRS with guanidinoacetate peak also noted for two patients. In addition, one proband was shown to have deficient GAMT activity in fibroblasts (PMID:19027335, 19388150, 24071436, 24268530, 24415674) (PP4_Strong). Each of these individuals is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic or likely pathogenic by the ClinGen CCDS VCEP including c.327G>A (2 patients; PMID:24071436, 24268530, 24415674), c.299dup13 (a.k.a. c.299_311dup) (PMID:19388150), and c.507_521dup15 (p.Cys169_Ser173dup) (PMID:19027335)(PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00011 (2/18390 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). When the variant was expressed in GAMT-deficient fibroblasts, GAMT enzyme activity was undetectable (PMID:24415674). The computational predictor REVEL gives a score of 0.856 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). Another variant at the same amino acid position, c.403G>T (p.Asp135Tyr), has been classified as likely pathogenic by the ClinGen CCDS VCEP (and would be likely pathogenic even without the use of PM5, therefore avoiding circular logic) (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 573140). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0); PP4_Strong, PM3, PP3, PS3_Supporting, PM2_Supporting, PM5_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 8, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA9043671/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 6.05

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 Pathogenic. Variant got 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.403G>A	p.Asp135Asn	missense_variant	Exon 4 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.403G>A	p.Asp135Asn	missense_variant	Exon 4 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.403G>A	p.Asp135Asn	missense_variant	Exon 4 of 6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251006 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461284 Hom.: 0 Cov.: 34 AF XY: 0.0000303 AC XY: 22 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000765 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Pathogenic:5

Jun 08, 2023

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000156.6(GAMT):c.403G>A variant in GAMT is predicted to result in the substitution of aspartate by asparagine at amino acid 135 (p.Asp135Asn). Four probands and one affected sibling have been reported with this variant, all with clinical symptoms consistent with GAMT deficiency, evidence of elevated guanidinoacetate and low creatine in plasma and/or urine, and reduced creatine on brain MRS with guanidinoacetate peak also noted for two patients. In addition, one proband was shown to have deficient GAMT activity in fibroblasts (PMID: 19027335, 19388150, 24071436, 24268530, 24415674) (PP4_Strong). Each of these individuals is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic or likely pathogenic by the ClinGen CCDS VCEP including c.327G>A (2 patients; PMID: 24071436, 24268530, 24415674), c.299dup13 (a.k.a. c.299_311dup) (PMID: 19388150), and c.507_521dup15 (p.Cys169_Ser173dup) (PMID: 19027335)(PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00011 (2/18390 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). When the variant was expressed in GAMT-deficient fibroblasts, GAMT enzyme activity was undetectable (PMID: 24415674). The computational predictor REVEL gives a score of 0.856 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). Another variant at the same amino acid position, c.403G>T (p.Asp135Tyr), has been classified as likely pathogenic by the ClinGen CCDS VCEP (and would be likely pathogenic even without the use of PM5, therefore avoiding circular logic) (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 573140). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0); PP4_Strong, PM3, PP3, PS3_Supporting, PM2_Supporting, PM5_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 8, 2023) -

Oct 04, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PM2,PS3_SUP,PP3 -

Cerebral creatine deficiency syndrome Pathogenic:2

Nov 02, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Asp135Asn variant in GAMT has been reported in 5 individuals with cerebral creatine deficiency syndrome (PMID: 19388150, 24415674, 24268530, 19027335, 24071436), segregated with disease in 1 affected relative from 1 family (PMID: 19388150), and has been identified in 0.01% (2/18390) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs774144200). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 5 affected individuals, 4 were compound heterozygotes that carried reported pathogenic variants with unknown phase, which increases the likelihood that the p.Asp135Asn variant is pathogenic (VariationID: 21065, 8302; PMID: 19388150, 24415674, 24268530, 19027335, 24071436). This variant has also been reported in ClinVar (Variation ID#: 573140) and has been interpreted as VUS by Invitae. In vitro functional studies provide some evidence that the p.Asp135Asn variant may slightly impact protein function (PMID: 24268530). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals homozygous or compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 19027335, 24071436, 24415674, 19388150). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM3_strong, PS3_supporting, PP3, PP4_strong, PM2_supporting (Richards 2015). -

Jul 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 135 of the GAMT protein (p.Asp135Asn). This variant is present in population databases (rs774144200, gnomAD 0.006%). This missense change has been observed in individual(s) with guanidinoacetate methyltransferase deficiency (PMID: 19388150, 24071436, 24415674, 35588794). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 573140). 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 affects GAMT function (PMID: 24415674). This variant disrupts the p.Asp135 amino acid residue in GAMT. Other variant(s) that disrupt this residue have been observed in individuals with GAMT-related conditions (PMID: 19027335), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;H
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.4	D;.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0050	D;.;D
Sift4G	Benign	0.074	T;.;T
Polyphen		1.0	D;.;.
Vest4		0.96
MVP		0.98
MPC		0.63
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.73
gMVP		0.90

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: rs774144200; hg19: chr19-1399183;