Submissions for variant NM_000481.4(AMT):c.635T>C (p.Val212Ala)

gnomAD frequency: 0.00024  dbSNP: rs201141125

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000638278	SCV000759771	pathogenic	Non-ketotic hyperglycinemia	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 212 of the AMT protein (p.Val212Ala). This variant is present in population databases (rs201141125, gnomAD 0.1%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 12948742, 26179960, 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: 531771). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AMT protein function. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000638278	SCV001309989	uncertain significance	Non-ketotic hyperglycinemia	2017-08-24	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV001312022	SCV001502438	uncertain significance	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000638278	SCV001520701	uncertain significance	Non-ketotic hyperglycinemia	2020-01-20	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV000638278	SCV002805599	uncertain significance	Non-ketotic hyperglycinemia	2022-05-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002529876	SCV003681033	uncertain significance	Inborn genetic diseases	2021-06-18	criteria provided, single submitter	clinical testing	The c.635T>C (p.V212A) alteration is located in exon 6 (coding exon 6) of the AMT gene. This alteration results from a T to C substitution at nucleotide position 635, causing the valine (V) at amino acid position 212 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV003492123	SCV003826276	uncertain significance	Glycine encephalopathy 2	2023-11-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155257	SCV003844848	uncertain significance	not specified	2023-02-16	criteria provided, single submitter	clinical testing	Variant summary: AMT c.635T>C (p.Val212Ala) 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 0.0003 in 250906 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AMT causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (0.0003 vs 0.0014), allowing no conclusion about variant significance. c.635T>C has been reported in the literature in at least one individual affected with Glycine Encephalopathy, consisten with being in trans (Non-Ketotic Hyperglycinemia) (Toone_2003, Coughlin_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six submitters classified the variant as VUS while one classified as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000638278	SCV001460883	uncertain significance	Non-ketotic hyperglycinemia	2020-01-02	no assertion criteria provided	clinical testing