rs121909272

chr19-1398980-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000156.6(GAMT):c.506G>A(p.Cys169Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C169R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 5.84

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 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000156.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1398981-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 818179.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 19-1398980-C-T is Pathogenic according to our data. Variant chr19-1398980-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8304.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-1398980-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAMT	NM_000156.6	c.506G>A	p.Cys169Tyr	missense_variant	5/6	ENST00000252288.8
GAMT	NM_138924.3	c.506G>A	p.Cys169Tyr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8	c.506G>A	p.Cys169Tyr	missense_variant	5/6	1	NM_000156.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250898 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461162 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726868

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 01, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	May 25, 2023	The NM_000156.6:c.505T>A variant in GAMT is a missense variant predicted to cause substitution of a cysteine by tyrosine at amino acid 169 (p.Cys169Tyr). This variant has been detected in 4 unrelated individuals with GAMT deficiency (PMID: 15651030, PMID: 24415674, PMID: 24268530, PMID: 24268530). These individuals were homozygous for the variant (1pt, PM3) (PMID: 15651030, PMID: 24415674, PMID: 24268530, PMID: 24268530). One of the individuals reported showed deficient (<5% wild-type) GAMT activity in lymphoblasts and elevated GAA in plasma and elevated GAA in urine (PMID: 15651030); one individual showed absent creatine peak on brain MRS and elevated urine GAA (PMID: 24415674); and one individual showed absent creatine peak on brain MRS (PMID: 32606525) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (2/34566 alleles) in the Latino/Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in GAMT-deficient fibroblasts resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674)(PS3_Supporting). The computational predictor REVEL gives a score of 0.754 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: 8304, 2 star review status) with 2 submitters classifying the variant as pathogenic and 3 submitters classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely 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): PS3_Supporting, PM2_Supporting, PM3, PP3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023) -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Dec 11, 2018	This variant was identified in composite heterozygosity with another variant in the same gene in a female patient with IDD. The unaffected parents are both carriers of one of the two variants in the same gene, while the affected brother also harbours both variants in composite heterozygosity -

Cerebral creatine deficiency syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 02, 2021	The p.Cys169Tyr variant in GAMT has been reported in 4 individuals with cerebral creatine deficiency syndrome (PMID: 15651030, 24415674, 24268530, 32606525), segregated with disease in 1 affected relative from 1 family (PMID: 32606525), and has been identified in 0.006% (2/34566) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121909272). 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 4 affected individuals, all of those were homozygotes which increases the likelihood that the p.Cys169Tyr variant is pathogenic (PMID: 15651030, 24415674, 24268530, 32606525). This variant has also been reported in ClinVar (Variation ID#: 8304) and has been interpreted as pathogenic by OMIM and Center of Genomic Medicine (Geneva, University Hospital of Geneva). In vitro functional studies provide some evidence that the p.Cys169Tyr 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, 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: 24415674, 2426853, 15651030, 32606525). 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, PM2_supporting, PP3, PS3_supporting, PP4_strong (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This variant disrupts the p.Cys169 amino acid residue in GAMT. Other variant(s) that disrupt this residue have been observed in individuals with GAMT-related conditions (PMID: 23660394), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GAMT function (PMID: 24415674). 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. ClinVar contains an entry for this variant (Variation ID: 8304). This missense change has been observed in individual(s) with Cerebral creatine deficiency syndrome (PMID: 15651030, 23234264, 24415674). This variant is present in population databases (rs121909272, gnomAD 0.006%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 169 of the GAMT protein (p.Cys169Tyr). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.092	D
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.9	D;.;N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0070	D;.;T
Sift4G	Uncertain	0.0040	D;.;T
Polyphen		1.0	D;.;.
Vest4		0.90
MutPred		0.88		Loss of stability (P = 0.1633);.;Loss of stability (P = 0.1633);
MVP		0.92
MPC		0.83
ClinPred		0.78	D
GERP RS		4.0
Varity_R		0.85
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121909272; hg19: chr19-1398979;