rs141066224

Positions:

• chr19-1397495-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.575C>T variant in GAMT is a missense variant that is predicted to cause the substitution of a threonine by a methionine at amino acid position 192 (p.Thr192Met). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest continental population minor allele frequency in gnomAD v4.1.0. is 0.0002665 (20/75058 alleles; no homozygotes) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Although the allele frequency in the Ashkenazi Jewish population in gnomAD v4.1.0. is higher at 0.002467 (73/29588 alleles; no homozygotes) (meeting BS1, >0.001) this frequency is not counted because it was found in a non-continental population (Ghosh et al, 2018, PMID:30311383). The computational predictor REVEL gives a score of 0.677 which is above the threshold of 0.644, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 205582). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting, PP3.(Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314808/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:8 B:1
• Conservation: PhyloP100: 9.54

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.575C>T	p.Thr192Met	missense_variant	6/6	ENST00000252288.8	NP_000147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.575C>T	p.Thr192Met	missense_variant	6/6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000640762.1	c.506C>T	p.Thr169Met	missense_variant	6/6	5		ENSP00000492031.1
GAMT	ENST00000640164.1	n.408C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

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: 0.000478

GnomAD3 exomes AF: 0.000149 AC: 36 AN: 241982 Hom.: 0 AF XY: 0.000159 AC XY: 21 AN XY: 131878

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00250

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000772 AC: 112 AN: 1451112 Hom.: 0 Cov.: 31 AF XY: 0.0000858 AC XY: 62 AN XY: 722278

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000233

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74490

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000155

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Uncertain:4

Uncertain significance, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Sep 11, 2024	The NM_000156.6:c.575C>T variant in GAMT is a missense variant that is predicted to cause the substitution of a threonine by a methionine at amino acid position 192 (p.Thr192Met). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest continental population minor allele frequency in gnomAD v4.1.0. is 0.0002665 (20/75058 alleles; no homozygotes) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Although the allele frequency in the Ashkenazi Jewish population in gnomAD v4.1.0. is higher at 0.002467 (73/29588 alleles; no homozygotes) (meeting BS1, >0.001) this frequency is not counted because it was found in a non-continental population (Ghosh et al, 2018, PMID: 30311383). The computational predictor REVEL gives a score of 0.677 which is above the threshold of 0.644, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 205582). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting, PP3. (Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 03, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2016

The p.T192M variant (also known as c.575C>T), located in coding exon 6 of the GAMT gene, results from a C to T substitution at nucleotide position 575. The threonine at codon 192 is replaced by methionine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs141066224. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.03% (4/13002) total alleles studied, having been observed in 0.05% (2/4406) African American alleles and 0.02% (2/8596) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cerebral creatine deficiency syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.7	M;.
PROVEAN	Uncertain	-2.6	D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		1.0	D;.
Vest4		0.81
MVP		0.95
ClinPred		0.18	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs141066224; hg19: chr19-1397494;