Submissions for variant NM_002693.3(POLG):c.3139C>T (p.Arg1047Trp)

gnomAD frequency: 0.00010  dbSNP: rs181860632

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188603	SCV000242226	likely pathogenic	not provided	2024-11-25	criteria provided, single submitter	clinical testing	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: 20818383, 31571979, 19251978, 22189570, 18195149, 29655203, 32347949, 35186329, 34690748, 37229156, 32613234, 38385069, 35861376, 36964972)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000188603	SCV000281261	pathogenic	not provided	2015-08-19	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000188603	SCV000705543	uncertain significance	not provided	2017-09-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633548	SCV000754794	pathogenic	Progressive sclerosing poliodystrophy	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1047 of the POLG protein (p.Arg1047Trp). This variant is present in population databases (rs181860632, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 18195149, 19478085, 22189570, 36964972). 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: 206548). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000188603	SCV000802079	likely pathogenic	not provided	2020-06-08	criteria provided, single submitter	clinical testing	PS4_moderate, PM2, PM3, PM5, PP5
Ambry Genetics	RCV002317146	SCV000851544	uncertain significance	Inborn genetic diseases	2022-07-27	criteria provided, single submitter	clinical testing	The c.3139C>T (p.R1047W) alteration is located in exon 20 (coding exon 19) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 3139, causing the arginine (R) at amino acid position 1047 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000633548	SCV000887120	likely pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3139C>T (NP_002684.1:p.Arg1047Trp) [GRCH38: NC_000015.10:g.89319065G>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18195149 . This variant meets the following evidence codes reported in the ACMG-guideline. 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 Likely Pathogenic.
3billion, Medical Genetics	RCV001808470	SCV002059151	likely pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with POLG related disorder (PMID:18195149, PS1_P). A different missense change at the same codon has been reported to be associated with POLG related disorder (PMID:12707443, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.848, 3CNET: 0.788, PP3_P). A missense variant is a common mechanism associated with Progressive external ophthalmoplegia (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000046, PM2_M). . The variant has been reported to be in trans with a pathogenic variant as compound heterozygous (3billion dataset, PM3_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
AiLife Diagnostics, AiLife Diagnostics	RCV000188603	SCV002503548	uncertain significance	not provided	2021-06-20	criteria provided, single submitter	clinical testing
Mendelics	RCV002247605	SCV002517373	likely pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	2022-05-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000633548	SCV004046715	likely pathogenic	Progressive sclerosing poliodystrophy		criteria provided, single submitter	not provided
Baylor Genetics	RCV000633548	SCV004205842	likely pathogenic	Progressive sclerosing poliodystrophy	2024-03-12	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000188603	SCV004229893	likely pathogenic	not provided	2024-05-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple individuals with clinical features associated with autosomal recessive POLG-related disorders. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987434	SCV004803263	uncertain significance	not specified	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: POLG c.3139C>T (p.Arg1047Trp) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251358 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related (4e-05 vs 0.0035), allowing no conclusion about variant significance. c.3139C>T has been reported in the literature in compound heterozygous individuals affected with Alpers disease (e.g. Wiltshire_2008) or progressive external ophthalmoplegia (e.g. Stewart_2009), or as a heterozygous genotype in an individual affected with mitochondrial complex I disorder without strong evidence for causality (e.g. Calvo_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20818383, 29655203, 19251978, 18195149). ClinVar contains an entry for this variant (Variation ID: 206548). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796081	SCV005416315	likely pathogenic	Progressive sclerosing poliodystrophy; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Moderate+PM3+PP4
CeGaT Center for Human Genetics Tuebingen	RCV000188603	SCV005436019	likely pathogenic	not provided	2024-09-01	criteria provided, single submitter	clinical testing	POLG: PM3:Strong, PM2
Fulgent Genetics, Fulgent Genetics	RCV004796081	SCV005633373	likely pathogenic	Progressive sclerosing poliodystrophy; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2024-03-21	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483565	SCV004228843	not provided	Progressive sclerosing poliodystrophy; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Spinocerebellar ataxia with epilepsy		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-30-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004732764	SCV005355988	likely pathogenic	POLG-related disorder	2024-05-28	no assertion criteria provided	clinical testing	The POLG c.3139C>T variant is predicted to result in the amino acid substitution p.Arg1047Trp. This variant was previously reported in the compound heterozygous or homozygous state in patients who presented with autosomal recessive Alpers’ syndrome, sensory neuropathy, or developmental delay and ataxia (Wiltshire et al. 2008. PubMed ID: 18195149; Lax et al. 2012. PubMed ID: 22189570; Supplementary data, Gorukmez et al. 2023. PubMed ID: 36964972). The c.3139C>T variant was also reported in two siblings who presented with progressive external ophthalmoplegia and/or ataxia; both patients harbored a second causative variant, although segregation analysis was not preformed (Stewart et al. 2009. PubMed ID: 19251978). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. A different amino acid substitution at this position (p.Arg1047Gln) was also reported to be causative for disease (Agostino et al. 2003. PubMed ID: 12707443). This variant is interpreted as likely pathogenic.