rs779931959

Variant names:

• chr19-1398964-C-CCAGGAGGTGAGGTTG
• rs779931959
• NM_000156.6:c.507_521dupCAACCTCACCTCCTG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM4 PP5_Very_Strong

The NM_000156.6(GAMT):​c.507_521dupCAACCTCACCTCCTG​(p.Cys169_Ser173dup) variant causes a disruptive 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 4.72
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000156.6
• 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 VariationId is 431959.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.507_521dupCAACCTCACCTCCTG	p.Cys169_Ser173dup	disruptive_inframe_insertion	Exon 5 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.507_521dupCAACCTCACCTCCTG	p.Cys169_Ser173dup	disruptive_inframe_insertion	Exon 5 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.507_521dupCAACCTCACCTCCTG	p.Cys169_Ser173dup	disruptive_inframe_insertion	Exon 5 of 6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250890 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461130 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 726870

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Pathogenic:3

Sep 11, 2024

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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 unrelated individuals with clinical symptoms consistent with GAMT deficiency. One individual had elevated plasma GAA and was compound heterozygous for the variant and a pathogenic variant in GAMT, c.327G>A (p.Lys109=, ClinVar ID: 21065), with the variants confirmed in trans by parental testing (PMID: 23583224, 29506905; personal communication) (PM3). The other individual had elevated plasma GAA and reduced cerebral creatine by MRS, pretreatment (PP4_Strong), and was compound heterozygous for the variant and c.403G>T (p.Asp135Tyr) (PMID: 19027335, 23660394); however, 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 and thus this individual was not counted towards PM3 evidence. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001525 (14/1180016 alleles; no homozygotes) 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 predictor PROVEAN predicts a damaging effect on GAMT function, but MutationTaster suggested no impact, such that PP3 is not met. 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 2.0.0): PP4_Strong, PM3, PM4, PM2_supporting. (Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024). -

Aug 05, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GAMT c.507_521dup (p.Cys169_Ser173dup) variant has been reported in trans with likely pathogenic or pathogenic variants in two unrelated individuals with cerebral creatine deficiency syndrome 2 (Dhar SU et al., PMID: 19027335; El-Gharbawy AH et al., PMID: 23583224). This variant is only observed on 1 out of 250,890 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant is predicted to cause a change in the length of the protein due to an in-frame duplication of five amino acids in a non-repeat region. This variant has been reported in the ClinVar database as a germline pathogenic variant by one submitter, likely pathogenic by four submitters, including an expert panel, and a variant of uncertain significance by one submitter. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. -

Jul 11, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cerebral creatine deficiency syndrome Pathogenic:2

Mar 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 02, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

not provided Pathogenic:1

Aug 11, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 31, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		4.7
Mutation Taster		=31/69	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs779931959; hg19: chr19-1398963;