ClinVar Miner

Submissions for variant NM_000481.4(AMT):c.664C>T (p.Arg222Cys)

gnomAD frequency: 0.00001  dbSNP: rs781466698
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668200 SCV000792762 likely pathogenic Glycine encephalopathy 2017-07-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000668200 SCV000962354 pathogenic Glycine encephalopathy 2024-01-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 222 of the AMT protein (p.Arg222Cys). This variant is present in population databases (rs781466698, gnomAD 0.004%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 25231368, 26179960, 27362913). ClinVar contains an entry for this variant (Variation ID: 552860). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AMT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668200 SCV002511515 pathogenic Glycine encephalopathy 2022-04-05 criteria provided, single submitter clinical testing Variant summary: AMT c.664C>T (p.Arg222Cys) results in a non-conservative amino acid change located in the Aminomethyltransferase, folate-binding domain (IPR006222) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251108 control chromosomes (gnomAD). c.664C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia, Azize_2014, Swanson_2015, Coughlin_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed this variant since 2014: one classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005004333 SCV002810910 pathogenic Glycine encephalopathy 2 2024-05-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV004568513 SCV004194540 pathogenic Glycine encephalopathy 1 2024-03-30 criteria provided, single submitter clinical testing
Natera, Inc. RCV000668200 SCV001456313 pathogenic Glycine encephalopathy 2020-09-16 no assertion criteria provided clinical testing

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