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

gnomAD frequency: 0.00017  dbSNP: rs75430333

Total submissions: 5

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 Laboratory Services, 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	2022-07-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 377 of the PDHX protein (p.Ile377Val). This variant is present in population databases (rs75430333, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected 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, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 Laboratories, Mayo Clinic	RCV000676200	SCV000801953	uncertain significance	not provided	2016-02-22	no assertion criteria provided	clinical testing