ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.2281G>A (p.Gly761Arg) (rs386833549)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671712 SCV000796717 likely pathogenic Non-ketotic hyperglycinemia 2017-12-22 criteria provided, single submitter clinical testing
Invitae RCV000671712 SCV001227323 pathogenic Non-ketotic hyperglycinemia 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 761 of the GLDC protein (p.Gly761Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs386833549, ExAC 0.1%). This variant has been observed in multiple individuals affected 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. ClinVar contains an entry for this variant (Variation ID: 555815). This variant has been reported to affect GLDC protein function (PMID: 26179960). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000671712 SCV001372378 pathogenic Non-ketotic hyperglycinemia 2020-06-19 criteria provided, single submitter clinical testing Variant summary: GLDC c.2281G>A (p.Gly761Arg) results in a non-conservative amino acid change in 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 0.00017 in 250606 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GLDC causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (0.00017 vs 0.0031), allowing no conclusion about variant significance. c.2281G>A has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (e.g. Applegarth_2001, Coughlin_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant had no measurable residual activity (Swanson_2015). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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