ClinVar Genomic variation as it relates to human health

The c.470T>G (p.V157G) alteration is located in exon 3 (coding exon 3) of the DLAT gene. This alteration results from a T to G substitution at nucleotide position 470, causing the valine (V) at amino acid position 157 to be replaced by a glycine (G). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the DLAT c.470T>G alteration was not observed among 6,498 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ _x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The V157 amino acid position is highly conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ biotin / lipoyl attachment domain (InterPro) The alteration is predicted deleterious by in silico models:_x000D_ The p.V157G alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as likely pathogenic.

Variant summary: DLAT c.470T>G (p.Val157Gly) results in a non-conservative amino acid change located in the Biotin/lipoyl attachment domain (IPR000089) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes in gnomAD. c.470T>G has been reported in the homozygous state in two siblings affected with features of Pyruvate Dehydrogenase E2 Deficiency, however only one sibling had biochemical analysis confirming the diagnosis (example: Friedman_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29093066). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic and likely pathogenic, respectively. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 157 of the DLAT protein (p.Val157Gly). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DLAT protein function. ClinVar contains an entry for this variant (Variation ID: 208790). This missense change has been observed in individual(s) with pyruvate dehydrogenase deficiency (PMID: 29093066). This variant is not present in population databases (gnomAD no frequency).