ClinVar Miner

Submissions for variant NM_000481.3(AMT):c.887G>A (p.Arg296His) (rs386833690)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049651 SCV000800767 likely pathogenic Non-ketotic hyperglycinemia 2017-06-02 criteria provided, single submitter clinical testing
GeneDx RCV000436156 SCV000512023 uncertain significance not provided 2016-05-30 criteria provided, single submitter clinical testing The R296H variant in the AMT gene has been reported previously in trans with another AMT variant in a family with glycine encephalopathy (Toone et al., 2013). The R296H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R296H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret R296H as a variant of uncertain significance.
Invitae RCV000049651 SCV000813475 pathogenic Non-ketotic hyperglycinemia 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 296 of the AMT protein (p.Arg296His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs386833690, ExAC 0.004%). This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with glycine encephalopathy or non-ketotic hyperglycinemia (PMID: 12948742) and in homozygosis or in trans with another rare AMT variant in several individuals affected with this condition (PMID: 26179960, 27362913, 16450403). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 56239). 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. The observation of one or more missense substitutions at this codon (p.Arg296Cys and p.Arg296His) in affected individuals suggests that this may be a clinically significant residue (PMID: 28244183, 26179960, 27362913, 16450403, 12948742). For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049651 SCV000082058 probable-pathogenic Non-ketotic hyperglycinemia no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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