ClinVar Genomic variation as it relates to human health
NM_000156.6(GAMT):c.491del (p.Gly164fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000156.6(GAMT):c.491del (p.Gly164fs)
Variation ID: 810628 Accession: VCV000810628.17
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 19p13.3 19: 1398995 (GRCh38) [ NCBI UCSC ] 19: 1398994 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 6, 2020 May 1, 2024 May 25, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000156.6:c.491del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000147.1:p.Gly164fs frameshift NM_000156.4:c.491del NM_138924.3:c.491del NP_620279.1:p.Gly164fs frameshift NC_000019.10:g.1399000del NC_000019.9:g.1398999del NG_009785.1:g.7559del - Protein change
- G164fs
- Other names
- NM_000156.6(GAMT):c.491del
- p.Gly164fs
- Canonical SPDI
- NC_000019.10:1398994:CCCCCC:CCCCC
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
GAMT | - | - |
GRCh38 GRCh37 |
463 | 656 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (6) |
reviewed by expert panel
|
May 25, 2023 | RCV001030778.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 21, 2024 | RCV001766818.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
Feb 28, 2022 | RCV002255172.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Pathogenic
(May 25, 2023)
|
reviewed by expert panel
Method: curation
|
Deficiency of guanidinoacetate methyltransferase
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen
Accession: SCV004009592.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
The NM_000156.6:c.491del (p.Gly164AlafsTer14) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate … (more)
The NM_000156.6:c.491del (p.Gly164AlafsTer14) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed. (PVS1_Strong). This variant has been detected in in 7 unrelated individuals with GAMT deficiency, all of whom were homozygous for the variant (PMID: 29302074, PMID: 32214227, PMID: 15234333, PMID: 23660394, PMID: 15108290) (1pt, PM3). One of these individuals had elevated GAA in plasma, elevated GAA in urine, deficient GAMT enzyme activity (<5% wild-type) in fibroblasts, and significantly reduced creatine peak with present GAA peak on brain MRS (PMID: 15234333) and one of these individuals had elevated urine GAA and undetectable GAMT enzyme activity in fibroblasts (PMID: 15108290) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001607 (4/24886 alleles) in the African/African American 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: 810628, 2 star review status) with 7 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as 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 1.0): PVS1_Strong, PM2_Supporting, PM3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023) (less)
|
|
Pathogenic
(Aug 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of guanidinoacetate methyltransferase
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001821335.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: GAMT c.491delG (p.Gly164AlafsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: GAMT c.491delG (p.Gly164AlafsX14) results in 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. The variant allele was found at a frequency of 1.2e-05 in 250692 control chromosomes. c.491delG has been reported in the literature in multiple individuals affected with Guanidinoactetate Methyltransferase Deficiency (example, Item_2004, Hengel_2020, Mercimek-Mahmutoglu_2006, Comeaux_2013). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cerebral creatine deficiency syndrome
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061233.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.491del;p.(Gly164Alafs*14) is a null frameshift variant (NMD) in the GAMT gene and predicts alteration of the nonsense-mediate decay - NMD is present in a … (more)
The c.491del;p.(Gly164Alafs*14) is a null frameshift variant (NMD) in the GAMT gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 810628; PMID: 32214227; 23660394; 16855203) - PS4. The variant is present at low allele frequencies population databases (rs749390953– gnomAD 0.003942%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly164Alafs*14) was detected in trans with a pathogenic variant (PMID: 16855203) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
|
|
Pathogenic
(Nov 02, 2021)
|
criteria provided, single submitter
Method: curation
|
Cerebral creatine deficiency syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001999913.2
First in ClinVar: Nov 06, 2021 Last updated: Feb 01, 2022 |
Comment:
The p.Gly164fs variant in GAMT has been reported in at least 6 individuals with cerebral creatine deficiency syndrome (PMID: 15108290, 32214227, 16855203, 23660394), and has … (more)
The p.Gly164fs variant in GAMT has been reported in at least 6 individuals with cerebral creatine deficiency syndrome (PMID: 15108290, 32214227, 16855203, 23660394), and has been identified in in 0.02% (4/24886) of African/African-American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs768985121). 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 6 affected individuals, all of those were homozygotes, which increases the likelihood that the p.Gly164fs variant is pathogenic (PMID: 15108290, 32214227, 16855203, 23660394). This variant has also been reported in ClinVar (Variation ID#: 810628) and has been interpreted as pathogenic by Section for Clinical Neurogenetics (University of Tübingen) and Women's Health and Genetics (Laboratory Corporation of America, LabCorp). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 164 and leads to a premature termination codon 14 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GAMT gene is an established disease mechanism in autosomal recessive cerebral creatine deficiency syndrome. The phenotype of individuals homozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 23660394, 15108290). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PVS1_strong, PM3, PP4_strong, PM2_supporting (Richards 2015). (less)
|
|
Pathogenic
(Feb 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002526593.2
First in ClinVar: Jun 24, 2022 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation, as the last 73 amino acids are replaced with 13 different amino acids, and other loss-of-function variants … (more)
Frameshift variant predicted to result in protein truncation, as the last 73 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 15234333, 23660394, 19027335, 26003046, 16054853, 15108290, 29302074, 32214227) (less)
|
|
Pathogenic
(Oct 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of guanidinoacetate methyltransferase
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004198571.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jan 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cerebral creatine deficiency syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002230002.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gly164Alafs*14) in the GAMT gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Gly164Alafs*14) in the GAMT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the GAMT protein. This variant is present in population databases (rs749390953, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with guanidinoacetate methyltransferase (GAMT) deficiency (PMID: 15108290, 23660394). ClinVar contains an entry for this variant (Variation ID: 810628). This variant disrupts a region of the GAMT protein in which other variant(s) (p.Trp174*) have been determined to be pathogenic (PMID: 17171576, 19027335, 23660394, 24268530). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Apr 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of guanidinoacetate methyltransferase
Affected status: yes
Allele origin:
germline
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV004934100.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Sex: male
Geographic origin: Iran
|
|
Pathogenic
(Aug 01, 2019)
|
no assertion criteria provided
Method: research
|
Deficiency of guanidinoacetate methyltransferase
Affected status: yes
Allele origin:
germline
|
Section for Clinical Neurogenetics, University of Tübingen
Accession: SCV001156085.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
|
|
Pathogenic
(Oct 07, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Guanidinoacetate methyltransferase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002087023.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery. | Hengel H | European journal of human genetics : EJHG | 2020 | PMID: 32214227 |
Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. | Stockler-Ipsiroglu S | Molecular genetics and metabolism | 2014 | PMID: 24268530 |
Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes. | Comeaux MS | Molecular genetics and metabolism | 2013 | PMID: 23660394 |
Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. | Dhar SU | Molecular genetics and metabolism | 2009 | PMID: 19027335 |
Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy. | Morris AA | Journal of inherited metabolic disease | 2007 | PMID: 17171576 |
GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis. | Mercimek-Mahmutoglu S | Neurology | 2006 | PMID: 16855203 |
Characterization of seven novel mutations in seven patients with GAMT deficiency. | Item CB | Human mutation | 2004 | PMID: 15108290 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ba2aa4f2-0344-4711-bce0-c8ecf71aebb4 | - | - | - | - |
Text-mined citations for rs749390953 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.