Submissions for variant NM_002693.3(POLG):c.1646del (p.Leu549fs)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521597	SCV000618433	likely pathogenic	not provided	2017-04-21	criteria provided, single submitter	clinical testing	The c.1646delT variant in the POLG gene has not been reported previously as a pathogenic variantnor as a benign variant, to our knowledge. The c.1646delT variant causes a frameshift starting withcodon Leucine 549, changes this amino acid to a Cysteine residue, and creates a premature Stop codonat position 4 of the new reading frame, denoted p.Leu549CysfsX4. This variant is predicted to causeloss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.The c.1646delT variant is not observed in large population cohorts (Lek et al., 2016; 1000 GenomesConsortium et al., 2015; Exome Variant Server). We interpret c.1646delT as a likely pathogenicvariant.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000678335	SCV000804399	likely pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	2017-08-03	criteria provided, single submitter	provider interpretation	This 10 year old male has a history of autism spectrum disorder, epilepsy, growth hormone deficiency, hypothyroidism, and ADHD combined type. Patient has had multiple EEGs that reportedly showed centrotemporal spikes that were considered epileptiform, though no seizures have been noted. He has reportedly had two normal MRIs. He is heterozygous for a nonsense POLG variant (c.1646delT) that was paternally inherited. His 45 year old father is reportedly healthy and is in a physically rigorous profession. A second variant, including a deletion or duplication of one or more exons, has not been excluded in this patient. This variant is absent from gnomAD and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, whole exome sequencing also identified another de novo variant of uncertain significance.

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