Submissions for variant NM_000481.4(AMT):c.602_603del (p.Lys201fs)

dbSNP: rs1279743247

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV001312233	SCV001502668	pathogenic	Glycine encephalopathy	2021-03-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001312233	SCV003310644	pathogenic	Glycine encephalopathy	2022-03-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1013618). This variant has not been reported in the literature in individuals affected with AMT-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Lys201Thrfs*75) in the AMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AMT are known to be pathogenic (PMID: 16450403).
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001312233	SCV003924218	pathogenic	Glycine encephalopathy	2022-06-10	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in 1 individual in the homozygous state (Stranneheim 2021 PMID: 33726816). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.003% [1/30616]; https://gnomad.broadinstitute.org/variant/3-49456785-GTT-G?dataset=gnomad_r2_1); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is also present in ClinVar (Variation ID: 1013618). Evolutionary conservation and computational predictive tools are unavailable for this variant. This variant creates a premature stop codon 75 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Coughlin 2017 PMID: 27362913). In summary, this variant is classified as pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003888014	SCV004704618	pathogenic	Glycine encephalopathy 2	2024-02-21	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in the homozygous state in at least one individual with features consistent with nonketotic hyperglycinemia (Stranneheim 2021 PMID: 33726816). It is present in gnomAD (Highest reported MAF: 0.007% [6/86258]; https://gnomad.broadinstitute.org/variant/3-49419352-GTT-G?dataset=gnomad_r4); please note, disease-causing variants may be present in control databases at low frequencies, reflective of carrier status, incomplete penetrance, and/or variable expressivity. It is also present in ClinVar (Variation ID: 1013618). This variant is a deletion of two nucleotides which is expected to alter the reading frame and introduce a premature stop codon 75 amino acid positions downstream from this location, resulting in protein truncation or loss of allelic expression through nonsense-mediated mRNA decay; loss of function is a known mechanism of disease for this gene (Coughlin 2017 PMID: 27362913). In summary, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001312233	SCV005726406	pathogenic	Glycine encephalopathy	2024-11-13	criteria provided, single submitter	clinical testing	Variant summary: AMT c.602_603delAA (p.Lys201ThrfsX75) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250724 control chromosomes. c.602_603delAA has been reported in the literature in a homozygous individual affected with Non-Ketotic Hyperglycinemia (Stanneheim_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33726816). ClinVar contains an entry for this variant (Variation ID: 1013618). Based on the evidence outlined above, the variant was classified as pathogenic.