rs80338735

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM2PP3_StrongPP5_Very_StrongBS1_Supporting

The NM_000156.6(GAMT):c.327G>A(p.Lys109=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000452 in 1,562,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

GAMT
NM_000156.6 splice_region, synonymous

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:15O:2

Conservation

PhyloP100: 4.65

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 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 19-1399793-C-T is Pathogenic according to our data. Variant chr19-1399793-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21065.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-1399793-C-T is described in Lovd as [Pathogenic]. Variant chr19-1399793-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000483 (681/1410270) while in subpopulation NFE AF= 0.000614 (667/1086398). AF 95% confidence interval is 0.000575. There are 0 homozygotes in gnomad4_exome. There are 310 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAMT	NM_000156.6 linkuse as main transcript	c.327G>A	p.Lys109=	splice_region_variant, synonymous_variant	2/6	ENST00000252288.8
GAMT	NM_138924.3 linkuse as main transcript	c.327G>A	p.Lys109=	splice_region_variant, synonymous_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8 linkuse as main transcript	c.327G>A	p.Lys109=	splice_region_variant, synonymous_variant	2/6	1	NM_000156.6	P1	Q14353-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000185

AC:

AN:

172966

Hom.:

AF XY:

0.000173

AC XY:

AN XY:

92628

show subpopulations

Gnomad AFR exome

AF:

0.0000996

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:

0.000410

Gnomad OTH exome

AF:

0.000425

GnomAD4 exome

AF:

0.000483

AC:

681

AN:

1410270

Hom.:

Cov.:

AF XY:

0.000445

AC XY:

310

AN XY:

697226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000620

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:

0.000614

Gnomad4 OTH exome

AF:

0.000205

GnomAD4 genome

AF:

0.000164

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000963

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:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000355

Hom.:

Bravo

AF:

0.000121

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase

Pathogenic:9Other:2

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	research	Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics	Jun 17, 2020	- -
not provided, no classification provided	phenotyping only	GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	-	Variant interpreted as Pathogenic and reported on 12-08-2009 by GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The GAMT c.327G>A (p.Lys109=) variant is reported as one of the most frequently observed pathogenic variants among patients with guanidinoacetate methyltransferase deficiency accounting for 24% of disease associated alleles (Mercimek-Mahmutoglu and Salomons 2015). Across a selection of the available literature, the p.Lys109= variant has been identified in a total of 15 individuals including four in a homozygous state and 11 in a compound heterozygous state (Stockler et al. 1996; Morris et al. 2007; Dhar et al. 2009; Comeaux et al. 2013; Mercimek-Mahmutoglu et al. 2014). Unaffected heterozygous carriers of the variant were observed in two families (Stockler et al. 1996). Control data are unavailable for this variant, which is reported at a frequency of 0.00031 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant affects the last nucleotide of the splice donor site of exon 2. Experimental analysis showed the variant results in two abnormal transcripts, one from the use of a cryptic splice site in intron 2 and one resulting from skipping of exon 2. Both abnormal transcripts were identified in one compound heterozygous individual and one homozygous individual, demonstrating the effect on splicing of the variant (Stockler et al. 1996). Based on the collective evidence, the p.Lys109= variant is classified as pathogenic for guanidinoacetate methyltransferase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1997	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_000156.6:c.327G>A (p.Lys109=) variant in GAMT is a synonymous variant that alters the last nucleotide of exon 2. It is one of the most common variants associated with GAMT deficiency, accounting for 31-35% of alleles (PMID: 19027335, 24268530). The variant has been previously reported in at least 30 unrelated GAMT deficiency patients, including among those with elevated urine guanidinoacetate, reduced or absent cerebral creatine peak on MRS (some of whom also have evidence of guanidinoacetate peak on MRS, and GAMT deficiency in fibroblasts (PMIDs: 8651275, 17171576, 19027335, 22019491, 23660394, 24268530, 24766785) (PP4_Strong) including at least 8 homozygotes (PMID: 8651275, 11978605, 19027335, 22019491, 24268530), and in compound heterozygosity with another variant that has been classified as pathogenic by the ClinGen CCDS VCEP including c.58dupT (PMID 24766785, confirmed in trans), c.297_c.309dup13 (PMID: 8651275, confirmed in trans; PMID: 19027335), c.522G>A (p.Trp174Ter) (PMID: 17171576, 19027335, 24268530; 3 probands), or c.36_c.37ins26 (PMID: 19027335) as well as c.133T>A (p.Trp45Arg) (PMID 24268530), and c.403G>A (p.Asp135Asn) (PMID 24268530) (PM3_VeryStrong). Additional patients may be reported in the literature but the maximum evidence for PM3_VeryStrong has already been reached. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00039 (34/ 86230 alleles) 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). The c.327G>A variant was shown by RT-PCR and RNA sequencing analysis to result in two abnormal transcripts: in one transcript, the variant resulted in a cryptic splice site in intron 2 and deletion of 146bp, and in the other transcript, the variant resulted in a 44bp insertion leading to altered splicing and skipping of exon 2 (PMID: 8651275) (PS3). It is predicted to alter splicing by SpliceAI (donor loss, score 0.93) and varSEAK (splicing class 5) (PP3). There is a ClinVar entry for this variant (Variation ID: 21065). In summary, this variant meets the criteria to be classified as Pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): PM3_VeryStrong, PS3, PP4_Strong, PP3, 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 01, 2018	Variant summary: GAMT c.327G>A (p.Lys109Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. These predictions are confirmed in a publication via RT-PCR analysis (though the results were not presented for evaluation; Stockler_1996). The same publication presented data showing that the activity of GAMT is significantly reduced in two patient's liver cells compared to WT, suggesting the variant affects protein function. The variant allele was found at a frequency of 0.00019 in 197356 control chromosomes. The c.327G>A variant has been reported in the literature in numerous individuals affected with Guanidinoactetate methyltransferase deficiency, both as homozygous and compound heterozygous alleles. These data indicate that the variant is very likely to be associated with disease. Additionally, in the literature it has been referred to as one of the most common mutations associated with Guanidinoactetate methyltransferase deficiency. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, both of which classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2020	RNA studies indicate that this variant causes abnormal gene splicing (Stockler et al., 1996; Dhar et al., 2009); This variant is associated with the following publications: (PMID: 25852444, 28055022, 22019491, 11978605, 8651275, 24766785, 24268530, 26319512, 16855203, 28119378, 19027335, 32606525, 31980526) -

Cerebral creatine deficiency syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change affects codon 109 of the GAMT mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAMT protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80338735, gnomAD 0.04%). This variant has been observed in individuals with guanidinoacetate methyltransferase deficiency (PMID: 2476685, 8651275, 22019491, 24415674). ClinVar contains an entry for this variant (Variation ID: 21065). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in an insertion of 44 nucleotides or a deletion of 146 nucleotides and introduces a premature termination codon (PMID: 8651275). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 02, 2021	The p.Lys109= variant in GAMT has been reported in >10 individuals with cerebral creatine deficiency syndrome (PMID: 8651275, 1978605, 24268530, 1902733, 23660394), segregated with disease in 4 affected relatives from 4 families (PMID: 24268530, 19027335), and has been identified in 0.04% (34/86230) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338735). 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 affected individuals, at least 12 of those were homozygotes, and at least 8 were compound heterozygotes that carried reported pathogenic/likely pathogenic variants in trans or with unknown phase, which increases the likelihood that the p.Lys109= variant is pathogenic (VariationID: 328352, 431959, 8302; PMID: 8651275, 1978605, 24268530, 1902733, 23660394). This variant has also been reported in ClinVar (Variation ID#: 21065) and has been interpreted as pathogenic by Illumina Clinical Services Laboratory, (Illumina), Integrated Genetics (Laboratory Corporation of America), Cytogenetics and Genomics Lab (Cyprus Institute Of Neurology and Genetics), Fulgent Genetics, GeneDx, Invitae, GeneReviews, Natera, Inc. In vitro functional studies provide evidence that the p.Lys109= variant impacts protein function (PMID: 8651275). However, these types of assays may not accurately represent biological function. This variant is located in the last three bases of the exon, which is part of the 3’ splice region. Computational tools do suggest an impact to splicing. 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, 22019491, 24766785, 8651275, 19027335). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM3_strong, PS3, PP3, PM2_supporting, PP4 (Richards 2015). -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2020

The c.327G>A (p.K109K) alteration is located in coding exon 2 of the GAMT gene. This alteration consists of a G to A substitution at nucleotide position 327. This nucleotide substitution does not change the lysine at codon 109. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. Based on data from the Genome Aggregation Database (gnomAD) database, the GAMT c.327G>A alteration was observed in 0.02% (38/204352) of total alleles studied, with a frequency of 0.04% (34/86230) in the European (non-Finnish) subpopulation. This mutation was identified in 30/82 alleles in a cohort of individuals with guanidinoacetate methyltransferase deficiency including numerous homozygous individuals (Stockler-Ipsiroglu, 2014). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

Cadd

Pathogenic

Dann

Benign

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.93

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.93

Position offset: 0

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