ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.391+1G>C

dbSNP: rs1600158894
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Total submissions: 2
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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 RCV002305546 SCV002600151 likely pathogenic Deficiency of guanidinoacetate methyltransferase 2022-06-06 reviewed by expert panel curation The NM_000156.6:c.391+1G>C variant in GAMT occurs within the canonical splice donor site of intron 3. Both SpliceAI and varSEAK predict the possible use of a cryptic site 7 bp downstream. If this site is used, or if exon 3 is skipped, this variant is predicted to result in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 664123). 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. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
Labcorp Genetics (formerly Invitae), Labcorp RCV000822144 SCV000962933 likely pathogenic Cerebral creatine deficiency syndrome 2019-02-07 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the GAMT gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with GAMT-related disease. 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAMT are known to be pathogenic (PMID: 15108290).

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