rs200833152
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BS3_Supporting
This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA295620/MONDO:0012999/026
Frequency
Consequence
NM_000156.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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GAMT | ENST00000252288.8 | c.79T>C | p.Tyr27His | missense_variant | Exon 1 of 6 | 1 | NM_000156.6 | ENSP00000252288.1 | ||
GAMT | ENST00000447102.8 | c.79T>C | p.Tyr27His | missense_variant | Exon 1 of 5 | 2 | ENSP00000403536.2 | |||
GAMT | ENST00000640762.1 | c.79T>C | p.Tyr27His | missense_variant | Exon 1 of 6 | 5 | ENSP00000492031.1 |
Frequencies
GnomAD3 genomes AF: 0.00339 AC: 516AN: 152024Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00282 AC: 245AN: 86858Hom.: 1 AF XY: 0.00268 AC XY: 134AN XY: 49930
GnomAD4 exome AF: 0.00456 AC: 5989AN: 1313380Hom.: 18 Cov.: 31 AF XY: 0.00438 AC XY: 2834AN XY: 647264
GnomAD4 genome AF: 0.00339 AC: 516AN: 152132Hom.: 4 Cov.: 32 AF XY: 0.00333 AC XY: 248AN XY: 74374
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
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GAMT: PP3, BS2 -
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Deficiency of guanidinoacetate methyltransferase Pathogenic:1Uncertain:1Benign:2
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). -
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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. -
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not specified Uncertain:1Benign:3
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. -
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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. -
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Inborn genetic diseases Benign:1
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. -
Cerebral creatine deficiency syndrome Benign:1
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Intellectual disability Benign:1
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GAMT-related disorder Benign:1
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). -
Guanidinoacetate methyltransferase (GAMT) deficiency Other:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at