Submissions for variant NM_000156.6(GAMT):c.64del (p.Ala22fs)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389180	SCV001590448	pathogenic	Cerebral creatine deficiency syndrome	2021-11-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala22Argfs*20) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1075552). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV004584892	SCV005073836	likely pathogenic	Deficiency of guanidinoacetate methyltransferase		criteria provided, single submitter	clinical testing	The observed frameshift variant c.64del(p.Ala22ArgfsTer20) in GAMT gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.64del variant has 0.001% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. However, study on multiple affected individuals and functional impact of the variant is not available. This variant causes a frameshift starting with codon Alanine 22, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 20 of the new reading frame, denoted p.Ala22ArgfsTer20. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Item CB, et al., 2004). For these reasons, this variant has been classified as Likely Pathogenic.

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