ClinVar Miner

Submissions for variant NM_003477.3(PDHX):c.1129A>G (p.Ile377Val) (rs75430333)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000676200 SCV000252058 uncertain significance not provided 2016-08-05 criteria provided, single submitter clinical testing The I377V variant in the PDHX gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I377V variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I377V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I377V as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000680150 SCV000371630 uncertain significance Pyruvate dehydrogenase E3-binding protein deficiency 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Baylor Genetics RCV000680150 SCV000807613 uncertain significance Pyruvate dehydrogenase E3-binding protein deficiency 2017-09-01 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it once in our laboratory homozygous in a 1-year-old male with regression, progressive encephalopathy, hypotonia, abnormal breathing requiring ventilation, a deceased older sister (not tested) with a similar presentation. However, lactic acidosis was not noted. Heterozygotes would be expected to be asymptomatic carriers.
Invitae RCV000676200 SCV000963289 uncertain significance not provided 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 377 of the PDHX protein (p.Ile377Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs75430333, ExAC 0.02%). This variant has not been reported in the literature in individuals with PDHX-related conditions. ClinVar contains an entry for this variant (Variation ID: 214958). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000676200 SCV000801953 uncertain significance not provided 2016-02-22 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.