Submissions for variant NM_002693.3(POLG):c.3436C>T (p.Arg1146Cys)

gnomAD frequency: 0.00014  dbSNP: rs2307440

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000513124	SCV000171115	uncertain significance	not provided	2023-12-11	criteria provided, single submitter	clinical testing	Identified heterozygous in an adult with diplopia, dysarthria, and dysphagia, loss skills, cerebellar dysarthria, severe horizontal and vertical external ophthalmoparesis, esotropia, slight left ptosis, and asymmetric facial muscle weakness. The proband's mother with strabismus was also heterozygous (PMID: 30838265); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21880868, 20843780, 15913923, 20220442, 25462018, 19275594, 31996268, 34828412, 16401742, 30838265, 34803902)
CeGaT Center for Human Genetics Tuebingen	RCV000513124	SCV000608733	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	POLG: PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545884	SCV000630148	uncertain significance	Progressive sclerosing poliodystrophy	2022-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1146 of the POLG protein (p.Arg1146Cys). This variant is present in population databases (rs2307440, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal dominant progressive external ophthalmoplegia and/or mitochondrial disease (PMID: 16401742, 20843780, 21880868, 30838265). ClinVar contains an entry for this variant (Variation ID: 21313). 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. Experimental studies have shown that this missense change affects POLG function (PMID: 25462018). 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.
Athena Diagnostics	RCV000513124	SCV000843334	uncertain significance	not provided	2023-02-28	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental analysis yielded inconclusive results regarding the impact of this variant on protein function. Functional analysis of the yeast homologue of this variant indicates that it is damaging to protein function; however, these results have not been confirmed in vitro in human cell types.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000545884	SCV000887300	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3436C>T (NP_002684.1:p.Arg1146Cys) [GRCH38: NC_000015.10:g.89318587G>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16401742 . This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). Based on the evidence criteria codes applied, the variant is suggested to be Benign.
Mendelics	RCV000545884	SCV001139676	benign	Progressive sclerosing poliodystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000545884	SCV001524400	uncertain significance	Progressive sclerosing poliodystrophy	2019-05-04	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with mitochondrial disorders [PMID 16401742]