ClinVar Miner

Submissions for variant NM_000284.4(PDHA1):c.839T>G (p.Ile280Ser) (rs1602229682)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel,ClinGen RCV001526402 SCV001736735 uncertain significance Pyruvate dehydrogenase complex deficiency 2021-04-02 reviewed by expert panel curation The c.839T>G (p.I280S) variant in the PDHA1 gene is a missense variant that has not been reported in population databases (PM2). One patient with an episodic gait disorder, speech delay, cognitive delay, elevated serum and CSF lactate and brain MRI findings consistent with Leigh syndrome has been reported in the literature with this variant (PMID: 20691944). This variant was also seen in his reportedly unaffected mother and two uncles with dystonia, which was insufficient to meet criteria of 4 or more segregations for PP1 per ClinGen SVI. Serum pyruvate levels were normal for this patient and no other biochemical studies were performed. In silico meta-predictors indicate a deleterious effect (PP3). In summary, this variant meets criteria to be classified as a variant of uncertain significance for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PM2, PP3). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021.
Invitae RCV000811945 SCV000952238 uncertain significance Pyruvate dehydrogenase E1-alpha deficiency 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with serine at codon 280 of the PDHA1 protein (p.Ile280Ser). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with clinical features of pyruvate dehydrogenase deficiency (PMID: 20691944, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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