Submissions for variant NM_000156.6(GAMT):c.419C>A (p.Ser140Ter)

dbSNP: rs747656257

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV000490258	SCV002600148	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2022-06-06	reviewed by expert panel	curation	The NM_000156.6 : c.419C>A (p.Ser140Ter) variant in GAMT is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant exon 4/6 that leads to nonsense mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the lietarture in individuals with GAMT deficiency. There is a ClinVar entry for this variant (Variation ID: 225369). 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).
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490258	SCV000267332	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2016-03-18	criteria provided, single submitter	reference population
Labcorp Genetics (formerly Invitae), Labcorp	RCV001211627	SCV001383176	pathogenic	Cerebral creatine deficiency syndrome	2023-05-22	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with GAMT-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 225369). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser140*) in the GAMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAMT are known to be pathogenic (PMID: 15108290).