rs80338736

Positions:

chr19-1399808-T-TGGGGCCCAGTCCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000156.6(GAMT):c.311_312insGGGACTGGGCCCC(p.Arg105GlyfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000999 in 1,572,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

GAMT
NM_000156.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:12

Conservation

PhyloP100: -0.826

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-1399808-T-TGGGGCCCAGTCCC is Pathogenic according to our data. Variant chr19-1399808-T-TGGGGCCCAGTCCC is described in ClinVar as [Pathogenic]. Clinvar id is 8302.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6 linkuse as main transcript	c.311_312insGGGACTGGGCCCC	p.Arg105GlyfsTer26	frameshift_variant	2/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3 linkuse as main transcript	c.311_312insGGGACTGGGCCCC	p.Arg105GlyfsTer26	frameshift_variant	2/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8 linkuse as main transcript	c.311_312insGGGACTGGGCCCC	p.Arg105GlyfsTer26	frameshift_variant	2/6	1	NM_000156.6	ENSP00000252288	P1	Q14353-1
GAMT	ENST00000447102.8 linkuse as main transcript	c.311_312insGGGACTGGGCCCC	p.Arg105GlyfsTer26	frameshift_variant	2/5	2		ENSP00000403536		Q14353-2
GAMT	ENST00000640762.1 linkuse as main transcript	c.242_243insGGGACTGGGCCCC	p.Arg82GlyfsTer26	frameshift_variant	2/6	5		ENSP00000492031
GAMT	ENST00000591788.3 linkuse as main transcript			upstream_gene_variant		5		ENSP00000466341

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000539

AC:

AN:

185556

Hom.:

AF XY:

0.0000801

AC XY:

AN XY:

99832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

150

AN:

1420072

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

702988

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000257

Gnomad4 ASJ exome

AF:

0.0000394

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000130

Gnomad4 OTH exome

AF:

0.000102

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cerebral creatine deficiency syndrome 2 (MIM#612736). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (11 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in multiple individuals with cerebral creatine deficiency (also known as GAMT deficiency, ClinVar, PMIDs: 24071436, 24276113, 29506905). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 22, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2021	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_000156.6:c.299_311dup (p. Arg105GlyfsTer26) in GAMT is a frameshift variant predicted to cause a premature stop codon in biologically relevant 3/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 4 probands with biochemical and clinical features consistent with GAMT deficiency have been reported, including patients with elevated plasma guanidinoacetate, and absent creatine peak and evidence of guanidinoacetate peak on magnetic resonance spectroscopy (PMIDs 8651275, 19027335, 19388150, 23660394, 29506905) (PP4_Strong). These patients include one homozygote (with a homozygous affected sibling) (PMID 23234264; 0.5 points; possibly same patient reported in PMID 29506905); and a proband who is compound heterozygous for the variant and c.327G>A (pathogenic based on assessment by the ClinGen CCDS VCEP), confirmed in trans (PMID 8651275, 19027335, 24268530) (PM3). Another patient is compound heterozygous for the variant and c.233T>A (p.Val78Glu)(PMID 23660394), and another patient and her affected sibling are compound heterozygous for the variant and c.403G>A (p.Asp135Asn) (PMID 19388150), The in trans data from the latter patients will be used in the analysis of p.Val78Glu and p.Asp135Asn and is not included here to avoid circular logic (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001175 in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 8302). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PM3, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2018	Variant summary: GAMT c.299_311dup13 (p.Arg105GlyfsX26) results in a frameshift generating a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.491dupG (p.Val165fsX26)). The variant was found at a frequency of 5.2e-05 (11/210322) control chromosomes in gnomAD, predominantly observed in the European (Non-Finnish) subpopulation (11/90660) with a frequency of 0.00012. This frequency is not significantly higher than expected for a pathogenic variant in GAMT causing Guanidinoactetate methyltransferase deficiency (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.299_311dup13 has been reported in the literature in multiple individuals affected with Guanidinoactetate methyltransferase deficiency either in homozygosity (Cheillan 2012) or in heterozygous form with other pathogenic (or likely pathogenic) GAMT variants in trans (e.g. Dhar 2009, Stockler 2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2017, and both of them classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -

Cerebral creatine deficiency syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 02, 2021	The p.Arg105fs variant in GAMT has been reported in 5 individuals with cerebral creatine deficiency syndrome (PMID: 8651275, 19027335, 23234264, 23660394, 24268530), segregated with disease in 2 affected relatives from 2 families (PMID: 23234264, 24268530), and has been identified in in 0.01% (11/93592) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs779679242). 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 5 affected individuals, at least 1 of those was a homozygote and 2 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg105fs variant is pathogenic (Variation ID: 21065; PMID: 8651275, 19027335, 23234264, 23660394, 24268530). This variant has also been reported in ClinVar (Variation ID#: 8302) and has been interpreted as pathogenic by Integrated Genetics (Laboratory Corporation of America), OMIM, Invitae, and GeneReviews. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 105 and leads to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAMT gene is a strongly established disease mechanism in autosomal recessive cerebral creatine deficiency syndrome. 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: 23660394, 8651275, 19027335, 23660394). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PVS1, PM3_strong, PM2_supporting, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Arg105Glyfs*26) in the GAMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAMT are known to be pathogenic (PMID: 15108290). This variant is present in population databases (rs756953118, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with guanidinoacetatemethyltransferase (GAMT) deficiency (PMID: 8651275, 19027335, 23234264, 23660394). It has also been observed to segregate with disease in related individuals. This variant is also known as 309ins13 or c.297_309dup. ClinVar contains an entry for this variant (Variation ID: 8302). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2018

The c.299_311dup13 variant, located in coding exon 2 of the GAMT gene, results from a duplication of GGGACTGGGCCCC at nucleotide position 299, causing a translational frameshift with a predicted alternate stop codon (p.R105Gfs*26). This alteration has been detected as homozygous in two individuals with GAMT deficiency (Cheillan D, Orphanet J Rare Dis 2012 Dec;7:96). In addition, this alteration has been detected in conjunction with other GAMT alterations in several individuals with GAMT deficiency and creatine deficiency syndromes (Comeaux MS, Mol. Genet. Metab. 2013 Jul;109(3):260-8; Dhar SU, Mol. Genet. Metab. 2009 Jan;96(1):38-43; Stöckler S,Am. J. Hum. Genet. 1996 May;58(5):914-22). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 29, 2021

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19027335, 8651275, 23660394, 29655203, 23234264) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over