ClinVar Miner

Submissions for variant NM_001482.3(GATM):c.778C>T (p.Arg260Ter)

gnomAD frequency: 0.00001  dbSNP: rs775933965
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen RCV002305458 SCV002600080 likely pathogenic Arginine:glycine amidinotransferase deficiency 2022-06-06 reviewed by expert panel curation The NM_001482.3: c.778C>T (p.Arg260Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5/9, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 (1/113680 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the published literature. There is a ClinVar entry for this variant (Variation ID: 205617). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
GeneDx RCV000187602 SCV000241197 pathogenic not provided 2012-09-24 criteria provided, single submitter clinical testing p.Arg260Stop (CGA>TGA):c.778 C>T in exon 5 of the GATM gene (NM_001482.2). The Arg260Stop nonsense mutation in the GATM gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this mutation has not been reported previously to our knowledge, it is considered a disease-causing mutation. The variant is found in CHILD-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV002305458 SCV004368218 pathogenic Arginine:glycine amidinotransferase deficiency 2023-04-10 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with GATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 205617). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg260*) in the GATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GATM are known to be pathogenic (PMID: 11555793). This variant is not present in population databases (gnomAD no frequency).

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