19-1401329-T-G

Variant names:

• chr19-1401329-T-G
• rs104894694
• NM_000156.6:c.148A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3_Supporting PP4_Strong PP3 PM2_Supporting PM3_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:4 U:1
• Conservation: PhyloP100: 7.68
• Publications: 3 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 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000156.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.148A>C	p.Met50Leu	missense	Exon 1 of 6	NP_000147.1
	GAMT	NM_138924.3		c.148A>C	p.Met50Leu	missense	Exon 1 of 5	NP_620279.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.148A>C	p.Met50Leu	missense	Exon 1 of 6	ENSP00000252288.1
	GAMT	ENST00000447102.8	TSL:2	c.148A>C	p.Met50Leu	missense	Exon 1 of 5	ENSP00000403536.2
	GAMT	ENST00000640762.1	TSL:5	c.112+36A>C		intron	N/A	ENSP00000492031.1

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

African (AFR) AF: 0.00 AC: 0 AN: 28946

American (AMR) AF: 0.00 AC: 0 AN: 37992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24316

East Asian (EAS) AF: 0.00 AC: 0 AN: 32806

South Asian (SAS) AF: 0.00 AC: 0 AN: 78540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4664

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079272

Other (OTH) AF: 0.00 AC: 0 AN: 57072

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Deficiency of guanidinoacetate methyltransferase (4)
-	1	-	Cerebral creatine deficiency syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.94		Loss of phosphorylation at Y49 (P = 0.0991)
MVP		0.91
MPC		0.18
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		-0.00070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.74
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894694; hg19: chr19-1401328;