rs1441030187

Positions:

• chr19-1399896-G-A
• chr19-1399896-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM3_Supporting PP3 PP4_Strong PM2_Supporting PS3

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.224C>T variant in GAMT is a missense variant that is predicted to result in the substitution of alanine by valine at amino acid 75 (p.Ala75Val). One patient, with mild intellectual disability, anti-epileptic drug-responsive seizures, and stereotypic movements has been reported with creatine and guanidinoacetate peak absent on MRS, bilateral thalami increased on MRI, and urine guanidinoacetate levels between 1.1 and 12 times above the upper limit of reference range (PP4_Strong). This individual is homozygous for the variant (PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 (1/15028 alleles) in the African population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). GAMT-deficient fibroblasts transfected with the variant showed <15% wild-type enzyme activity (PMID:24415674). The computational predictor REVEL gives a score of 0.86 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 544251). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PP3, PS3_Supporting, PM2_Supporting, PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA402996954/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: GAMT ENST00000252288.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:2
• Conservation: PhyloP100: 9.88

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 11 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.
• 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/exons	MANE	Protein	UniProt
GAMT	NM_000156.6	c.224C>T	p.Ala75Val	missense_variant	2/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.224C>T	p.Ala75Val	missense_variant	2/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.224C>T	p.Ala75Val	missense_variant	2/6	1	NM_000156.6	ENSP00000252288	P1
GAMT	ENST00000447102.8	c.224C>T	p.Ala75Val	missense_variant	2/5	2		ENSP00000403536
GAMT	ENST00000640762.1	c.155C>T	p.Ala52Val	missense_variant	2/6	5		ENSP00000492031

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32

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: 0.0000209 AC: 5 AN: 239744 Hom.: 0 AF XY: 0.0000230 AC XY: 3 AN XY: 130240

Gnomad AFR exome AF: 0.0000665

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000341

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000278

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000288 AC: 42 AN: 1456236 Hom.: 0 Cov.: 33 AF XY: 0.0000318 AC XY: 23 AN XY: 723922

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000704

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

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

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Pathogenic:3 Uncertain:1

Pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Mar 09, 2023	The NM_000156.6:c.224C>T variant in GAMT is a missense variant that is predicted to result in the substitution of alanine by valine at amino acid 75 (p.Ala75Val). One patient, with mild intellectual disability, anti-epileptic drug-responsive seizures, and stereotypic movements has been reported with creatine and guanidinoacetate peak absent on MRS, bilateral thalami increased on MRI, and urine guanidinoacetate levels between 1.1 and 12 times above the upper limit of reference range (PP4_Strong). This individual is homozygous for the variant (PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 (1/15028 alleles) in the African population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). GAMT-deficient fibroblasts transfected with the variant showed <15% wild-type enzyme activity (PMID: 24415674). The computational predictor REVEL gives a score of 0.86 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 544251). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PP3, PS3_Supporting, PM2_Supporting, PM3_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 09, 2024	Variant summary: GAMT c.224C>T (p.Ala75Val) results in a non-conservative amino acid change located in the Arginine N-methyltransferase 2-like domain (IPR026480) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 239744 control chromosomes. c.224C>T has been reported in the literature in a homozygous individual affected with Guanidinoactetate Methyltransferase Deficiency (Mercimek-Mahmutoglu_2014) and was identified in as an unspecified genotype in an individual undergoing multigene panel testing for epilepsy and neurodevelopmental disorders, although no further clinical information was provided (Lindy_2018) . These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The variant exhibited <4% activity versus the WT protein when transfected into a GAMT-deficient human fibroblast cell line (Mercimek-Mahmutoglu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 29655203, 24415674). ClinVar contains an entry for this variant (Variation ID: 544251). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 18, 2020	- -

Cerebral creatine deficiency syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 02, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 75 of the GAMT protein (p.Ala75Val). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with a positive newborn screening result for GAMT-related disease (PMID: 24415674). ClinVar contains an entry for this variant (Variation ID: 544251). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects 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. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 02, 2021	The p.Ala75Val variant in GAMT has been reported in 1 homozygous individual with cerebral creatine deficiency syndrome (PMID: 24415674) and has been identified in 0.007% (1/15028) of African/African-American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1441030187). 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. This variant has also been reported in ClinVar (Variation ID#: 544251) and has been interpreted as VUS by Invitae. In vitro functional studies provide some evidence that the p.Ala75Val variant may slightly impact protein function (PMID: 24415674). 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. 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: 24415674). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM3_supporting, PM2_supporting, PS3_supporting, PP3, PP4_strong (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.2	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0030	D;.;T
Sift4G	Uncertain	0.029	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.50		Gain of catalytic residue at A75 (P = 0.0098);.;Gain of catalytic residue at A75 (P = 0.0098);
MVP		0.93
MPC		0.63
ClinPred		0.87	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.71
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1441030187; hg19: chr19-1399895; COSMIC: COSV52040506; COSMIC: COSV52040506;