19-1397447-C-G

Variant names:

• chr19-1397447-C-G
• rs767887772
• NM_000156.6:c.623G>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_000156.6(GAMT):​c.623G>C​(p.Arg208Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV005903236: "When expressed in GAMT-deficient fibroblasts, the variant resulted in ~4% wild type GAMT activity (PMID 24415674) (PS3_Supporting)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208H) has been classified as Uncertain significance. The gene GAMT is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 0.126
• Publications: 0 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: Ambry Genetics, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for GAMT are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005903236: "When expressed in GAMT-deficient fibroblasts, the variant resulted in ~4% wild type GAMT activity (PMID 24415674) (PS3_Supporting)."
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1397447-C-G is Pathogenic according to our data. Variant chr19-1397447-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3775038.Status of the report is reviewed_by_expert_panel, 3 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.623G>C	p.Arg208Pro	missense	Exon 6 of 6	NP_000147.1	Q14353-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.623G>C	p.Arg208Pro	missense	Exon 6 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.893G>C	p.Arg298Pro	missense	Exon 6 of 6	ENSP00000572533.1
	GAMT	ENST00000902472.1		c.626G>C	p.Arg209Pro	missense	Exon 6 of 6	ENSP00000572531.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Deficiency of guanidinoacetate methyltransferase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.3
DANN	Benign	0.76
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.13
PROVEAN	Benign	-0.86	N
REVEL	Pathogenic	0.75
Sift	Benign	0.21	T
Sift4G	Benign	0.067	T
Polyphen		0.65	P
Vest4		0.11
MutPred		0.44		Gain of glycosylation at T209 (P = 0.0258)
MVP		0.48
ClinPred		0.42	T
GERP RS		-5.0
Varity_R		0.60
Mutation Taster		=34/66	disease causing

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: rs767887772; hg19: chr19-1397446;