Submissions for variant NM_000156.6(GAMT):c.172TCC[3] (p.Ser59dup)

dbSNP: rs768895098

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793456	SCV000932808	uncertain significance	Cerebral creatine deficiency syndrome	2022-08-22	criteria provided, single submitter	clinical testing	This variant, c.175_177dup, results in the insertion of 1 amino acid(s) of the GAMT protein (p.Ser59dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs768895098, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 640432). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002536964	SCV003739614	uncertain significance	Inborn genetic diseases	2021-02-11	criteria provided, single submitter	clinical testing	The c.175_177dupTCC (p.S59dup) alteration is located in exon 1 (coding exon 1) of the GAMT gene. The alteration consists of an in-frame duplication of 3 nucleotides from position 175 to 177, resulting in the duplication of 1 residue. Based on data from the Genome Aggregation Database (gnomAD) database, the GAMT c.175_177dupTCC alteration was observed in 0.01% (15/142718) of total alleles studied. This amino acid position is well conserved in available vertebrate species. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479219	SCV004223781	uncertain significance	not specified	2023-11-14	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.175_177dupTCC (p.Ser59dup) results in an in-frame duplication that is predicted to duplicate 1 amino acid into the encoded protein. The variant allele was found at a frequency of 0.00011 in 142718 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GAMT causing Cerebral Creatine Deficiency Syndrome 2 (0.00011 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.175_177dupTCC in individuals affected with Cerebral Creatine Deficiency Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV004588252	SCV005080236	uncertain significance	not provided	2023-12-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports a deleterious effect on protein structure/function; In-frame /insertion of 1amino acid in a non-repeat region
Natera, Inc.	RCV001830695	SCV002087055	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2020-02-26	no assertion criteria provided	clinical testing