ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.641C>T (p.Ala214Val)

dbSNP: rs948866053
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000459940 SCV000543868 uncertain significance Progressive sclerosing poliodystrophy 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 214 of the POLG protein (p.Ala214Val). 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: 405572). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. 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.
Undiagnosed Diseases Network, NIH RCV000550484 SCV000622172 uncertain significance Mitochondrial DNA depletion syndrome; Primary progressive multiple sclerosis 2016-01-28 criteria provided, single submitter clinical testing
GeneDx RCV002526395 SCV003195213 uncertain significance not provided 2022-07-19 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV003258816 SCV003948577 uncertain significance Inborn genetic diseases 2023-04-12 criteria provided, single submitter clinical testing The c.641C>T (p.A214V) alteration is located in exon 2 (coding exon 1) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 641, causing the alanine (A) at amino acid position 214 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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