rs779931959

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM4PP5_Very_Strong

The NM_000156.6(GAMT):c.521_522insCAACCTCACCTCCTG(p.Cys169_Ser173dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.0000112 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GAMT
NM_000156.6 inframe_insertion

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:5U:1

Conservation

PhyloP100: 4.72

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 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000156.6

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000156.6.

PP5

Variant 19-1398964-C-CCAGGAGGTGAGGTTG is Pathogenic according to our data. Variant chr19-1398964-C-CCAGGAGGTGAGGTTG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431959.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAMT	NM_000156.6 linkuse as main transcript	c.521_522insCAACCTCACCTCCTG	p.Cys169_Ser173dup	inframe_insertion	5/6	ENST00000252288.8
GAMT	NM_138924.3 linkuse as main transcript	c.521_522insCAACCTCACCTCCTG	p.Cys169_Ser173dup	inframe_insertion	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8 linkuse as main transcript	c.521_522insCAACCTCACCTCCTG	p.Cys169_Ser173dup	inframe_insertion	5/6	1	NM_000156.6	P1	Q14353-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250890

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135826

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461130

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726870

show subpopulations

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:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

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.Cys169_Ser173dup variant in GAMT has been reported in at least 3 individuals with cerebral creatine deficiency syndrome (PMID: 19027335, 23583224, 29506905) and has been identified in 0.0009% (1/113306) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs370421531). 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 3 affected individuals, 1 was a compound heterozygote that carried a pathogenic variant in trans, and 2 were compound heterozygotes that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Cys169_Ser173dup variant is pathogenic (Variation ID: 21065, 573140 PMID: 19027335, 23583224, 29506905). This variant has also been reported in ClinVar (Variation ID#: 431959) and has been interpreted as a VUS by Invitae and Ambry Genetics and likely pathogenic by GeneDx. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is an insertion of 5 amino acids at position 169 and is not predicted to alter the protein reading-frame. The phenotype of individuals compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 23583224, 29506905, 19027335). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM3, PM2_supporting, PM4, PP4_strong, PP3 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	This variant, c.507_521dup, results in the insertion of 5 amino acid(s) of the GAMT protein (p.Cys169_Ser173dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779931959, gnomAD 0.002%). This variant has been observed in individual(s) with creatine deficiency syndromes (PMID: 19027335, 23583224, 23660394). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 431959). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Deficiency of guanidinoacetate methyltransferase

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 11, 2023	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_000156.6:c.507_521dup (p.Cys169_Ser173dup) variant in GAMT is a protein length-changing variant (in-frame insertion) in a non-repeat region (PM4). This variant has been previously reported in at least two cases with clinical symptoms consistent with GAMT deficiency. One proband had elevated plasma GAA and was compound heterozygous for the variant and a pathogenic variant in GAMT, c.327G>A (p.Lys109=), with the variants confirmed in trans by parental testing (PMID: 23583224, 29506905; personal communication). Another proband had elevated plasma GAA and reduced cerebral creatine by MRS, pretreatment, and was compound heterozygous for the variant and c.403G>T (p.Asp135Tyr) (PMID: 19027335, 23660394) (PP4_Strong, PM3). The allelic data for the latter patient will be used in the classification of p.Asp135Tyr and was not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00000883 (1/113306 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 computational predictors PROVEAN and MutPred-Indel gave scores consistent with a damaging effect on GAMT function, but MutationTaster suggested no impact (PP3 was not applied). There is a ClinVar entry for this variant (Variation ID: 431959). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_strong, PM3, PM2_supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2023

In-frame insertion of 5 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19027335, 29506905, 23660394, 23583224) -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2017

The c.507_521dup15 variant (also known as p.C169_S173dup), located in coding exon 5 of the GAMT gene, results from an in-frame duplication of 15 nucleotides at nucleotide positions 507 to 521. This results in the duplication of 5 extra residues (CNLTS) between codons 169 and 173. These amino acid positions are highly conserved in available vertebrate species. This variant has been described in a patient with GAMT deficiency who was also heterozygous for a recurrent splice site alteration; however, the phase of the alterations was not specified (Dhar SU, et al. Mol. Genet. Metab. 2009 Jan;96(1):38-43). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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