ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.507_521dup (p.Cys169_Ser173dup) (rs779931959)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497566 SCV000589566 likely pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing The c.507_521dup15 variant in the GAMT gene has been reported previously in two unrelated individuals with guanidinoacetate methyltransferase (GAMT) deficiency who were also heterozygous for another variant in the GAMT gene (Dhar et al., 2009; El-Gharbawy et al., 2013). The c.507_521dup15 variant causes an in-frame duplication of five amino acid residues starting with codon Cysteine 169, denoted p.Cys169_Ser173dup. This duplication contains a substrate binding region. The c.507_521dup15 variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.507_521dup15 as a likely pathogenic variant.
Invitae RCV000695868 SCV000824392 uncertain significance Cerebral creatine deficiency syndrome 2018-06-29 criteria provided, single submitter clinical testing This variant, c.507_521dupCAACCTCACCTCCTG, results in the insertion of 5 amino acids to the GAMT protein (p.Cys169_Ser173dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779931959, ExAC 0.002%). This variant has been observed in combination with another GAMT variant in individuals affected with creatine deficiency syndromes (PMID: 19027335, 23660394, 23583224). ClinVar contains an entry for this variant (Variation ID: 431959). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids 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 RCV000718874 SCV000849738 uncertain significance History of neurodevelopmental disorder 2017-05-31 criteria provided, single submitter clinical testing The c.507_521dup15 variant (also known as p.C169_S173dup), located in coding exon 5 of the GAMT gene, results from an in-frame duplication of 15 nucleotides at nucleotide positions 507 to 521. This results in the duplication of 5 extra residues (CNLTS) between codons 169 and 173. These amino acid positions are highly conserved in available vertebrate species. This variant has been described in a patient with GAMT deficiency who was also heterozygous for a recurrent splice site alteration; however, the phase of the alterations was not specified (Dhar SU, et al. Mol. Genet. Metab. 2009 Jan;96(1):38-43). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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