Submissions for variant NM_000170.2(GLDC):c.806C>T (p.Thr269Met) (rs386833587)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000049513	SCV000793463	likely pathogenic	Non-ketotic hyperglycinemia	2017-08-16	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000049513	SCV000919469	pathogenic	Non-ketotic hyperglycinemia	2018-09-28	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.806C>T (p.Thr269Met) 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 1.6e-05 in 246244 control chromosomes. c.806C>T has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) both as a compound heterozygous and homozygous allele (Conter_2006, Coughlin_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 residual enzyme activity, where <10% of normal activity was observed in vitro (Swanson_2015). 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.
Invitae	RCV000049513	SCV000945814	pathogenic	Non-ketotic hyperglycinemia	2018-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 269 of the GLDC protein (p.Thr269Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs386833587, ExAC 0.02%). This variant has been observed to be homozygous and in combination with another GLDC variant in individuals affected with nonketotic hyperglycinemia (PMID: 16601880, 16450403, 27362913). ClinVar contains an entry for this variant (Variation ID: 56104). This variant has been reported to affect GLDC protein function (PMID: 26179960). For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049513	SCV000081949	probable-pathogenic	Non-ketotic hyperglycinemia		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.

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