rs757918826
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000481.4(AMT):c.794G>A(p.Arg265His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000481.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AMT | NM_000481.4 | c.794G>A | p.Arg265His | missense_variant | 7/9 | ENST00000273588.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AMT | ENST00000273588.9 | c.794G>A | p.Arg265His | missense_variant | 7/9 | 1 | NM_000481.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152146Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251324Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135876
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461814Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727210
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152146Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
Non-ketotic hyperglycinemia Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 265 of the AMT protein (p.Arg265His). This variant is present in population databases (rs757918826, gnomAD 0.01%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 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: 550886). 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. This variant disrupts the p.Arg265 amino acid residue in AMT. Other variant(s) that disrupt this residue have been observed in individuals with AMT-related conditions (PMID: 26371980, 27362913), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 15, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 15, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000550886 / PMID: 25231368). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25231368, 27362913). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 27362913). A different missense change at the same codon (p.Arg265Cys) has been reported to be associated with AMT related disorder (PMID: 26371980). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 15, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27362913, 25231368, 27535533) - |
Glycine encephalopathy 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 19, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at