Submissions for variant NM_152783.5(D2HGDH):c.1183C>T (p.Arg395Trp) (rs149628174)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV001082053	SCV000429408	benign	D-2-hydroxyglutaric aciduria 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000498804	SCV000590384	uncertain significance	not provided	2017-06-06	criteria provided, single submitter	clinical testing	The R395W variant in the D2HGDH gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R395W variant is observed in 108/8608 (1.25%) alleles from individuals of East Asian background, in the ExAC dataset (Lek et al., 2016). The R395W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R395W as a variant of uncertain significance.
Invitae	RCV001082053	SCV001030469	benign	D-2-hydroxyglutaric aciduria 1	2019-12-31	criteria provided, single submitter	clinical testing

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