ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.1545G>C (p.Arg515Ser) (rs121964976)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Claritas Genomics RCV000449527 SCV000537854 pathogenic Obesity; Global developmental delay; Generalized epilepsy 2016-11-28 criteria provided, single submitter clinical testing The c.1545G>C (p.Arg515Ser) missense variant in the GLDC gene is previously reported in the literature and is a recognized cause of nonketotic hyperglycinemia. Homozygous and compound heterozygous loss-of-function pathogenic variants in this gene are associated with nonketotic hyperglycinemia, also known as glycine encephalopathy. This variant has been observed at a high frequency among individuals with nonketotic hyperglycinemia and has been seen in both the homozygous and compound heterozygous state with other known pathogenic variants, including large exonic deletions. Functional studies have shown that the presence of this variant causes the protein to be unstable with no residual functional activity. This variant has not been observed in either 1000 Genomes or NHLBI Exome Sequencing Project datasets, but has been observed in ExAC at an allele frequency of 0.00015, with no homozygotes reported. This variant involves a weakly conserved nucleotide but highly conserved amino acid. PolyPhen-2, SIFT, and MutationTaster all predict this variant to be damaging. Therefore, based on the reports and functional evidence in the literature, this variant is classified as pathogenic.
Counsyl RCV000012765 SCV000789135 likely pathogenic Non-ketotic hyperglycinemia 2017-01-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000012765 SCV000894478 pathogenic Non-ketotic hyperglycinemia 2018-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000012765 SCV000086734 pathologic Non-ketotic hyperglycinemia 2013-07-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000012765 SCV000916266 pathogenic Non-ketotic hyperglycinemia 2018-10-31 criteria provided, single submitter clinical testing The GLDC c.1545G>C (p.Arg515Ser) variant has been reported in five studied and was found in a total of 60 probands including four in a homozygous state, 48 in a compound heterozygous state, and 11 in a heterozygous state with an undetected second allele (Toone et al. 2000; Toone et al. 2001, Sellner et al. 2005; Kanno et al. 2007; Coughlin et al. 2016). A large deletion may not have been identified in the heterozygous probands with the testing methods used (Toone et al. 2001, Sellner et al. 2005). The p.Arg515Ser variant is identified as a founder variant in the United Kingdom (Coughlin et al. 2016). Control data are unavailable for the p.Arg515Ser variant, which is reported at a frequency of 0.000189 in the European (non-Finnish) population of the Genome Aggregation Database. The crystal structure of the p.Arg515Ser variant predicts the variant protein to be destabilized (Nakai et al. 2005). Based on the evidence, the p.Arg515Ser variant is classified as pathogenic for glycine encephalopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000012765 SCV000919471 pathogenic Non-ketotic hyperglycinemia 2018-06-29 criteria provided, single submitter clinical testing Variant summary: GLDC c.1545G>C (p.Arg515Ser) 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 9e-05 in 277284 control chromosomes (gnomAD and publication). The variant, c.1545G>C, has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia)(Sellner_2005, Toone_2001). It has also been reported as a commonly observed missesne variant present in six percent of all GLDC alleles (PMID: 27362913, Coughlin et al, 2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000012765 SCV000636358 pathogenic Non-ketotic hyperglycinemia 2018-04-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 515 of the GLDC protein (p.Arg515Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs121964976, ExAC 0.01%). This variant is one of the most prevalent variants seen in individuals with glycine encephalopathy. It has been reported as homozygous or as heterozygous in combination with an unknown second allele and it has also been observed on the opposite chromosome (in trans) from pathogenic variants in individuals affected with glycine encephalopathy (nonketotic hyperglycininemia) (PMID: 10873393, 17361008, 12126939, 11286506, 26179960, Invitae). This latter finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 11985). Experimental studies have shown that this missense change results in severely deficient glycine exchange activity of the protein encoded by GLDC (PMID: 10873393). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012765 SCV000033000 pathogenic Non-ketotic hyperglycinemia 2001-04-01 no assertion criteria provided literature only

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