ClinVar Miner

Submissions for variant NM_000481.4(AMT):c.217C>T (p.Arg73Cys)

gnomAD frequency: 0.00003  dbSNP: rs386833679
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049640 SCV000636425 pathogenic Non-ketotic hyperglycinemia 2023-12-21 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 73 of the AMT protein (p.Arg73Cys). This variant is present in population databases (rs386833679, gnomAD 0.006%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 16450403, 27362913). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56228). 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.
CeGaT Center for Human Genetics Tuebingen RCV001090584 SCV001246198 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing AMT: PM3:Very Strong, PM2
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000049640 SCV001367597 likely pathogenic Non-ketotic hyperglycinemia 2020-04-02 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM3_STR,PM2,PP3.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV000049640 SCV001502669 pathogenic Non-ketotic hyperglycinemia 2021-03-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049640 SCV002050700 pathogenic Non-ketotic hyperglycinemia 2021-12-01 criteria provided, single submitter clinical testing Variant summary: AMT c.217C>T (p.Arg73Cys) 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 3.6e-05 in 251240 control chromosomes (gnomAD). c.217C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (example: Kure_2006, Coughlin_2017, Isik_2019, Stranneheim_2021). 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. Six ClinVar submitters have assessed this variant after 2014: four classified the variant as likely pathogenic and two have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251953 SCV002523424 likely pathogenic See cases 2019-12-26 criteria provided, single submitter clinical testing ACMG classification criteria: PS4, PM2, PM3, PP3
Baylor Genetics RCV000049640 SCV004196279 likely pathogenic Non-ketotic hyperglycinemia 2023-07-10 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049640 SCV000082047 probable-pathogenic Non-ketotic hyperglycinemia no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Counsyl RCV000049640 SCV000790201 likely pathogenic Non-ketotic hyperglycinemia 2017-03-17 no assertion criteria provided clinical testing
Natera, Inc. RCV000049640 SCV001460430 likely pathogenic Non-ketotic hyperglycinemia 2020-09-16 no assertion criteria provided clinical testing

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