ClinVar Miner

Submissions for variant NM_000481.4(AMT):c.1033+1G>C

dbSNP: rs2107928969
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001381218 SCV001579522 pathogenic Non-ketotic hyperglycinemia 2020-10-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with glycine encephalopathy (PMID: 27362913). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1034+1G>C and IVS8+1G>C. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 of the AMT gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001381218 SCV002507028 uncertain significance Non-ketotic hyperglycinemia 2022-05-04 criteria provided, single submitter curation The homozygous c.1033+1G>C variant in AMT was identified by our study in 1 individual with glycine encephalopathy. The variant has not been previously reported in individuals with glycine encephalopathy and was absent from large population studies. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the AMT gene is a moderately established disease mechanism in autosomal recessive glycine encephalopathy. The presence of this variant in 1 affected homozygote increases the likelihood that the c.1033+1G>C variant is pathogenic. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3_supporting, PVS1_supporting (Richards 2015).

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