ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2027C>T (p.Ala676Val) (rs376306906)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000733276 SCV000619733 uncertain significance not provided 2017-08-25 criteria provided, single submitter clinical testing The A676V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 9/11,556 (0.08%) alleles from individuals of Latino background, in large population cohorts (Lek et al., 2016). The A676V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000552401 SCV000630120 uncertain significance Progressive sclerosing poliodystrophy 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 676 of the POLG protein (p.Ala676Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs376306906, ExAC 0.08%). This variant has been reported in heterozygous state in an individual affected with develomental delay, hypotonia, encephalopathy, ataxia, seizure, myoclonus, pyramidal signs, intractable seizure, spasticity, and in another individual without symptoms (PMID: 21880868). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". 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. 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000733276 SCV000861322 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000552401 SCV000887036 likely benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2027C>T (NP_002684.1:p.Ala676Val) [GRCH38: NC_000015.10:g.89324150G>A] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. BP7:The variant is silent with non predicted splice impact. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.
Fulgent Genetics,Fulgent Genetics RCV000763992 SCV000894943 uncertain significance Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1 (MNGIE type); Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Cerebellar ataxia infantile with progressive external ophthalmoplegia; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2018-10-31 criteria provided, single submitter clinical testing

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