ClinVar Miner

Submissions for variant NM_000481.4(AMT):c.794G>A (p.Arg265His) (rs757918826)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665764 SCV000789933 likely pathogenic Non-ketotic hyperglycinemia 2017-03-15 criteria provided, single submitter clinical testing
Invitae RCV000665764 SCV001219862 pathogenic Non-ketotic hyperglycinemia 2019-01-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 265 of the AMT protein (p.Arg265His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs757918826, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another AMT variant in individual(s) with glycine encephalopathy (PMID: 27362913). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550886). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg265 amino acid residue in AMT. Other variant(s) that disrupt this residue have been observed in individuals with AMT-related conditions (PMID: 26371980, 27362913), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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