ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.587C>T (p.Ala196Val)

gnomAD frequency: 0.00009  dbSNP: rs565109128
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001704993 SCV000241167 likely benign not provided 2021-06-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26319512)
Invitae RCV000793466 SCV000932818 uncertain significance Cerebral creatine deficiency syndrome 2022-08-15 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 196 of the GAMT protein (p.Ala196Val). This variant is present in population databases (rs565109128, gnomAD 0.02%). 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: 205588). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect GAMT function (PMID: 26319512). 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.
CeGaT Center for Human Genetics Tuebingen RCV001704993 SCV002063700 uncertain significance not provided 2021-10-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV002354525 SCV002649469 uncertain significance Inborn genetic diseases 2017-09-28 criteria provided, single submitter clinical testing The p.A196V variant (also known as c.587C>T), located in coding exon 6 of the GAMT gene, results from a C to T substitution at nucleotide position 587. The alanine at codon 196 is replaced by valine, an amino acid with similar properties. This alteration has been reported in a heterozygous state in a pilot newborn screening program in the Netherlands (Mercimek-Mahmutoglu S et al. Gene, 2016 Jan;575:127-31). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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