Submissions for variant NM_002693.3(POLG):c.3409dup (p.Val1137fs)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484097	SCV000573655	likely pathogenic	not provided	2017-02-27	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the POLG gene. The c.3409dupG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3409dupG variant causes a frameshift starting with codon Valine 1137, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 36 of the new reading frame, denoted p.Val1137GlyfsX36. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.3409dupG variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the c.3409dupG variant has not been reported previously to our knowledge, other frameshift variants have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506657	SCV000604904	likely pathogenic	not specified	2017-03-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690284	SCV000817965	pathogenic	Progressive sclerosing poliodystrophy	2024-05-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val1137Glyfs*36) in the POLG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLG are known to be pathogenic (PMID: 18546365). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 423899). For these reasons, this variant has been classified as Pathogenic.

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