chr19-1398964-C-CCAGGAGGTGAGGTTG
Position:
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
NM_000156.6 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.72
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]
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 | c.521_522insCAACCTCACCTCCTG | p.Cys169_Ser173dup | inframe_insertion | 5/6 | ENST00000252288.8 | |
GAMT | NM_138924.3 | 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 | c.521_522insCAACCTCACCTCCTG | p.Cys169_Ser173dup | inframe_insertion | 5/6 | 1 | NM_000156.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152192
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250890Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135826
GnomAD3 exomes
AF:
AC:
1
AN:
250890
Hom.:
AF XY:
AC XY:
1
AN XY:
135826
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461130Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 726870
GnomAD4 exome
AF:
AC:
17
AN:
1461130
Hom.:
Cov.:
32
AF XY:
AC XY:
9
AN XY:
726870
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
GnomAD4 genome
AF:
AC:
1
AN:
152192
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74346
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
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, 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). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 11, 2023 | - - |
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:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at