rs104894694

Positions:

• chr19-1401329-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3 PP4_Strong PM2_Supporting PM3_Supporting PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.148A>C (p.Met50Leu) variant in GAMT has been previously reported in one individual with guanidinoacetate methyltransferase deficiency (PMID:17101918). This variant is absent from population databases (PM2_Supporting). The affected individual previously reported (PMID:17101918) was a homozygote for the variant and had a low creatine peak on brain MRS, elevated urinary GAA, low creatine/creatinine ratio, with DNA sequence analysis of GAMT (PM3_Supporting, PP4_Strong). The p.Met50Leu variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.923) (PP3). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID:24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3, PP4_Strong(Classification approved by the ClinGen CCDS VCEP on March 9, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA254380/MONDO:0012999/026

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.68

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 Likely_pathogenic. Variant got 8 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.148A>C	p.Met50Leu	missense_variant	1/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.148A>C	p.Met50Leu	missense_variant	1/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.148A>C	p.Met50Leu	missense_variant	1/6	1	NM_000156.6	ENSP00000252288	P1
GAMT	ENST00000447102.8	c.148A>C	p.Met50Leu	missense_variant	1/5	2		ENSP00000403536
GAMT	ENST00000640762.1	c.112+36A>C		intron_variant		5		ENSP00000492031

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1379532 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 685310

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 14, 2006	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Mar 09, 2023	The NM_000156.6:c.148A>C (p.Met50Leu) variant in GAMT has been previously reported in one individual with guanidinoacetate methyltransferase deficiency (PMID: 17101918). This variant is absent from population databases (PM2_Supporting). The affected individual previously reported (PMID: 17101918) was a homozygote for the variant and had a low creatine peak on brain MRS, elevated urinary GAA, low creatine/creatinine ratio, with DNA sequence analysis of GAMT (PM3_Supporting, PP4_Strong). The p.Met50Leu variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.923) (PP3). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3, PP4_Strong (Classification approved by the ClinGen CCDS VCEP on March 9, 2023) -

Cerebral creatine deficiency syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 29, 2021

This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with leucine at codon 50 of the GAMT protein (p.Met50Leu). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and leucine. This missense change has been observed in individual(s) with GAMT deficiency (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. Experimental studies have shown that this missense change affects GAMT function (PMID: 24415674). 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 8305). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.76	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.99	D;.
Vest4		0.84
MutPred		0.94		Loss of phosphorylation at Y49 (P = 0.0991);Loss of phosphorylation at Y49 (P = 0.0991);
MVP		0.91
MPC		0.18
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.74

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: rs104894694; hg19: chr19-1401328;