chr19-1398980-C-T

Variant names:

• chr19-1398980-C-T
• rs121909272
• NM_000156.6:c.506G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3_Supporting PP4_Strong PM3 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA254379/MONDO:0012999/026

• 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:10
• Conservation: PhyloP100: 5.84
• Publications: 6 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: Likely_pathogenic. The variant received 9 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 rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.506G>A	p.Cys169Tyr	missense_variant	Exon 5 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.506G>A	p.Cys169Tyr	missense_variant	Exon 5 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.506G>A	p.Cys169Tyr	missense_variant	Exon 5 of 6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250898 AF XY: 0.0000147

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Pathogenic:7

Mar 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 11, 2018

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

May 25, 2023

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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) -

May 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAMT c.506G>A (p.Cys169Tyr) results in a non-conservative amino acid change in 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 1.6e-05 in 250898 control chromosomes. c.506G>A has been reported in the literature in at-least two individuals affected with Cerebral Creatine Deficiency Syndrome (example, Caldeira Araujo_2005, Mercimek-Mahmutoglu_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in diminished normal activity in fibroblast cell line (Mercimek-Mahmutoglu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 15651030, 24415674). ClinVar contains an entry for this variant (Variation ID: 8304). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 28, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cerebral creatine deficiency syndrome Pathogenic:2

Nov 02, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change affects GAMT function (PMID: 24415674). 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. 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. 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). -

not provided Pathogenic:1

Jun 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate impaired protein expression and GAMT activity (Mercimek-Mahmutoglu et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 23234264, 24268530, 19027335, 24415674, 15651030, 32606525) -

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
PhyloP100		5.8
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909272; hg19: chr19-1398979;