ClinVar Genomic variation as it relates to human health
NM_000156.6(GAMT):c.79T>C (p.Tyr27His)
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
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NM_000156.6(GAMT):c.79T>C (p.Tyr27His)
Variation ID: 167131 Accession: VCV000167131.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.3 19: 1401398 (GRCh38) [ NCBI UCSC ] 19: 1401397 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 5, 2015 May 12, 2024 Feb 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000156.6:c.79T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000147.1:p.Tyr27His missense NM_138924.3:c.79T>C NP_620279.1:p.Tyr27His missense NC_000019.10:g.1401398A>G NC_000019.9:g.1401397A>G NG_009785.1:g.5156T>C Q14353:p.Tyr27His - Protein change
- Y27H
- Other names
- p.Y27H:TAC>CAC
- NM_000156.6(GAMT):c.79T>C
- Canonical SPDI
- NC_000019.10:1401397:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00300 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00200
1000 Genomes Project 30x 0.00265
Exome Aggregation Consortium (ExAC) 0.00268
The Genome Aggregation Database (gnomAD), exomes 0.00282
1000 Genomes Project 0.00300
The Genome Aggregation Database (gnomAD) 0.00345
Trans-Omics for Precision Medicine (TOPMed) 0.00357
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 | ||
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HI score
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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. |
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GAMT | - | - |
GRCh38 GRCh37 |
463 | 656 | |
LOC130062945 | - | - | - | GRCh38 | - | 163 |
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. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Feb 13, 2023 | RCV000153308.24 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000224880.31 | |
not provided (1) |
no classification provided
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- | RCV001009545.9 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001081204.15 | |
Benign (4) |
reviewed by expert panel
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Feb 8, 2023 | RCV001127426.15 | |
Likely benign (1) |
no assertion criteria provided
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Jan 1, 2019 | RCV001251994.9 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 3, 2018 | RCV002312992.9 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV003907448.1 |
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. |
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Benign
(Feb 08, 2023)
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reviewed by expert panel
Method: curation
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Deficiency of guanidinoacetate methyltransferase
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen
Accession: SCV003852727.1
First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023 |
Comment:
NM_000156.6:c.79T>C variant in GAMT is a missense variant that is predicted to result in the substitution of tyrosine by histidine at amino acid 27 (p.Tyr27His). … (more)
NM_000156.6:c.79T>C variant in GAMT is a missense variant that is predicted to result in the substitution of tyrosine by histidine at amino acid 27 (p.Tyr27His). This variant was identified in the homozygous state in an individual with normal GAMT enzyme activity in fibroblasts (PMID: 24415674). The variant is present in gnomAD v2.1.1. at a maximum population frequency of 0.00471 (>0.003, cutoff for BA1) and found in the homozygous state in 2 individuals in gnomAD v2.1.1 (BA1). In fibroblasts, overexpressing the GAMT c.79T>C (p.Tyr27His) variant, restored GAMT activity to similar levels as the wild-type GAMT transfection (PMID: 24415674)(BS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 167131). In summary, this variant meets the criteria to be classified as benign 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): BA1, BS3_Supporting. (Classification approved by the ClinGen CCDS VCEP on February 8, 2023). (less)
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Uncertain significance
(Sep 16, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000247450.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Uncertain Significance
(Apr 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281130.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Comment:
Converted during submission to Uncertain significance.
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Benign
(Mar 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV001143982.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
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Benign
(Feb 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844600.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: GAMT c.79T>C (p.Tyr27His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: GAMT c.79T>C (p.Tyr27His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 86858 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAMT causing Cerebral Creatine Deficiency Syndrome 2 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.79T>C in individuals affected with Cerebral Creatine Deficiency Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=1, VUS n=2, likely benign n=3, benign n=5). Based on the evidence outlined above, the variant was classified as benign. (less)
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cerebral creatine deficiency syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000562805.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
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Likely benign
(Jan 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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GAMT-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004728895.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Benign
(Feb 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000241179.7
First in ClinVar: Aug 07, 2015 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Benign
(Feb 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000202787.7
First in ClinVar: Feb 02, 2015 Last updated: Apr 09, 2018 |
Number of individuals with the variant: 5
Sex: mixed
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of guanidinoacetate methyltransferase
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001286738.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely benign
(Nov 03, 2018)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000849302.5
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001501211.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Comment:
GAMT: PP3, BS2
Number of individuals with the variant: 13
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Likely pathogenic
(Apr 01, 2020)
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no assertion criteria provided
Method: clinical testing
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Deficiency of guanidinoacetate methyltransferase
Affected status: no, yes
Allele origin:
maternal,
paternal
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Elsea Laboratory, Baylor College of Medicine
Accession: SCV001424220.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
Observation 1:
Sex: male
Testing laboratory: Org: 1006
Observation 2:
Sex: male
Testing laboratory: Org: 1006
Observation 3:
Sex: male
Testing laboratory: Org: 1006
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Likely benign
(Jan 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
uniparental
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001427740.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
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Benign
(Jan 11, 2020)
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no assertion criteria provided
Method: clinical testing
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Guanidinoacetate methyltransferase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001460089.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978379.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001980165.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Guanidinoacetate methyltransferase (GAMT) deficiency
Affected status: unknown
Allele origin:
germline
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GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies
Accession: SCV001169640.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
Variant interpreted as Uncertain significance and reported on 08-22-2014 by GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory … (more)
Variant interpreted as Uncertain significance and reported on 08-22-2014 by GTR ID 26957. 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. (less)
Clinical Features:
Abnormality of muscle physiology (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the pelvis (present) , Morphological … (more)
Abnormality of muscle physiology (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the pelvis (present) , Morphological abnormality of the central nervous system (present) , Abnormality of coordination (present) , Seizures (present) , Abnormality of movement (present) , Depressivity (present) , Hallucinations (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2014-08-22
Testing laboratory interpretation: Uncertain significance
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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 |
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Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene. | Mercimek-Mahmutoglu S | Human mutation | 2014 | PMID: 24415674 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAMT | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7c04e605-50d3-4535-babc-261b76fc7eee | - | - | - | - |
Text-mined citations for rs200833152 ...
HelpRecord last updated May 12, 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.