ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.2216G>A (p.Arg739His) (rs121964980)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000012770 SCV000956559 likely pathogenic Non-ketotic hyperglycinemia 2018-08-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 739 of the GLDC protein (p.Arg739His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121964980, ExAC 0.005%). This variant has been observed to be homozygous in an individual affected with nonketotic hyperglycinemia (PMID: 15824356). It has also been observed in another individual with nonketotic hyperglycinemia, but in this individual a second pathogenic allele was not identified (PMID: 16450403).  ClinVar contains an entry for this variant (Variation ID: 11990). Experimental studies have shown that this missense change disrupts normal GLDC protein function (PMID: 15824356). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV000012770 SCV001163615 likely pathogenic Non-ketotic hyperglycinemia criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012770 SCV001426767 pathogenic Non-ketotic hyperglycinemia 2020-07-03 criteria provided, single submitter clinical testing Variant summary: GLDC c.2216G>A (p.Arg739His) 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 3.6e-05 in 247686 control chromosomes. c.2216G>A has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (example, Dinopoulos_2005, Kure_2006, unpublished source from bioRxiv_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Dinopoulos_2005). The most pronounced variant effect results in <10% of normal GLDC enzyme activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001659692 SCV001872483 pathogenic not provided 2021-07-30 criteria provided, single submitter clinical testing Published functional studies demonstrate that the R739H variant had decreased enzymatic activity (Dinopoulos et al., 2005); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33977025, 30833958, 27535533, 16450403, 17074608, 15824356)
OMIM RCV000012770 SCV000033005 pathogenic Non-ketotic hyperglycinemia 2005-04-12 no assertion criteria provided literature only
Natera, Inc. RCV000012770 SCV001457119 likely pathogenic Non-ketotic hyperglycinemia 2020-09-16 no assertion criteria provided clinical testing

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