Submissions for variant NM_002693.3(POLG):c.1156C>T (p.Arg386Cys)

gnomAD frequency: 0.00002  dbSNP: rs199759055

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188650	SCV000242273	likely pathogenic	not provided	2022-07-11	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20837862, 32347949)
Eurofins Ntd Llc (ga)	RCV000188650	SCV000336723	uncertain significance	not provided	2018-01-29	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000188650	SCV000609536	uncertain significance	not provided	2017-04-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000660573	SCV000782685	uncertain significance	Progressive sclerosing poliodystrophy; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2017-06-19	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758259	SCV000886899	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.1156C>T (NP_002684.1:p.Arg386Cys) [GRCH38: NC_000015.10:g.89328699G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:20837862 . This variant meets the following evidence codes reported in the ACMG-guideline. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.
Illumina Laboratory Services, Illumina	RCV000778454	SCV000914702	uncertain significance	POLG-Related Spectrum Disorders	2018-11-20	criteria provided, single submitter	clinical testing	The POLG c.1156C>T (p.Arg386Cys) is a missense variant that has been reported in one study and found in one individual with isolated distal myopathy of the upper extremities in the absence of sensory disturbances in a compound heterozygous state with another missense variant (Giordano et al. 2010). This variant was inherited from the unaffected father in a heterozygous state and is reported at a frequency of 0.000182 in the South Asian population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Arg386Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000758259	SCV001227073	likely pathogenic	Progressive sclerosing poliodystrophy	2024-01-06	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 386 of the POLG protein (p.Arg386Cys). This variant is present in population databases (rs199759055, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 20837862). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 206589). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV000758259	SCV001522832	uncertain significance	Progressive sclerosing poliodystrophy	2020-06-20	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000188650	SCV002024706	likely pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989500	SCV004807272	uncertain significance	Mitochondrial DNA depletion syndrome 4b	2024-03-26	criteria provided, single submitter	clinical testing