Submissions for variant NM_002693.3(POLG):c.1402A>G (p.Asn468Asp)

gnomAD frequency: 0.00063  dbSNP: rs145843073

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658725	SCV000242282	likely pathogenic	not provided	2024-09-12	criteria provided, single submitter	clinical testing	Identified in three members of a family with CPEO, peripheral neuropathy, parkinsonism, and multiple mtDNA deletions in muscle who were also heterozygous for another POLG variant on the other allele; the authors could not conclusively determine whether p.(N468D) was related to the phenotype as siblings carrying p.(N468D) were unaffected (PMID: 15351195, 15181170); Identified as homozygous in an infant with Aicardi-Goutires syndrome who was also homozygous for a pathogenic variant in TREX1 (PMID: 33683010); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24122062, 19578034, 24508722, 28284481, 31669236, 32391929, 32347949, 29029963, 29712893, 16401742, 24259288, 21880868, 34426522, 22647225, 23811324, 19752458, 15181170, 32234506, 33513296, 23921535, 35114397, 36291626, 33683010, 35641312, 15351195, 24331360, 25193669, 31658717, 23426270, 30373890, 30255931, 29997391, 37138020)
Eurofins Ntd Llc (ga)	RCV000658725	SCV000331575	uncertain significance	not provided	2018-04-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470781	SCV000543881	likely benign	Progressive sclerosing poliodystrophy	2024-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000658725	SCV000614702	uncertain significance	not provided	2023-05-12	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. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) In multiple individuals, this variant has been seen where an alternate explanation for disease was also identified, suggesting this variant is unlikely to cause disease. Computational tools disagree on the variant's effect on normal protein function.
CeGaT Center for Human Genetics Tuebingen	RCV000658725	SCV000780512	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing	POLG: PM2:Supporting, BP4
Ambry Genetics	RCV002314743	SCV000848060	uncertain significance	Inborn genetic diseases	2022-07-24	criteria provided, single submitter	clinical testing	The c.1402A>G (p.N468D) alteration is located in exon 7 (coding exon 6) of the POLG gene. This alteration results from a A to G substitution at nucleotide position 1402, causing the asparagine (N) at amino acid position 468 to be replaced by an aspartic acid (D). The altered amino acid is not conserved throughout evolution:_x000D_ _x000D_ The p.N468 amino acid is not conserved in available vertebrate species. The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.N468D alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. 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	RCV000470781	SCV000886902	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.1402A>G (NP_002684.1:p.Asn468Asp) [GRCH38: NC_000015.10:g.89327198T>C] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15351195 ; 16401742 . This variant meets the following evidence codes reported in the ACMG-guideline. PS4:Prevalence of variant in affecteds statistically increased over controls. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763995	SCV000894946	uncertain significance	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1; 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	2018-10-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001610504	SCV001156973	uncertain significance	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	2021-09-01	criteria provided, single submitter	clinical testing	The POLG c.1402A>G; p.Asn468Asp variant is reported in the literature in individuals affected with autosomal recessive progressive external ophthalmoplegia (Luoma 2004, Palin 2013, Woodbridge 2013). The affected individuals identified in these reports were compound heterozygous for the p.Asn468Asp variant while heterozygous carriers in the same family were unaffected. The variant has also been shown to co-segregate with disease in families with autosomal recessive progressive external ophthalmoplegia (Wanrooij 2004). This variant is reported with conflicting interpretations in ClinVar (Variation ID: 206596). Another variant in this region, p.Ala467Thr, is considered the most common pathogenic POLG variant (Variation ID: 13496). However, due to limited functional evidence, the clinical significance of the p.Asn468Asp variant is uncertain.
Baylor Genetics	RCV001004603	SCV001163773	likely pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4b		criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027840	SCV001190460	uncertain significance	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	2021-03-30	criteria provided, single submitter	clinical testing	POLG NM_002693.2 exon 7 p.Asn468Asp (c.1402A>G): This variant has been reported in the literature in the compound heterozygous state in at least 3 individuals with autosomal recessive progressive external opthalmoplegia in addition to ataxia, tetraparesis, and/or parkinsonism, segregating with disease in two affected family members (Luoma 2004 PMID:15351195, Gonzalez-Viogue 2006 PMID:16401742, Woodbridge 2013 PMID:22647225). This variant has also been identified in multiple individuals with suspected POLG-deficiency who did not have a second identifiable variant in the POLG gene (Blok 2009 PMID:19578034, Tang 2011 PMID:21880868). This variant is present in 0.07% (18/25122) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-89870429-T-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar (Variation ID:206596). This variant amino acid Aspartic Acid (Asp) is present in several species including two mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Laboratory Services, Illumina	RCV001117972	SCV001276218	uncertain significance	POLG-Related Spectrum Disorders	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
New York Genome Center	RCV001263305	SCV001441346	uncertain significance	Seizure; Intellectual disability	2020-04-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001330959	SCV001522834	likely pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2020-11-04	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000658725	SCV001716240	uncertain significance	not provided	2023-06-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847836	SCV002105550	uncertain significance	Hereditary spastic paraplegia	2020-04-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001330959	SCV002581528	uncertain significance	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2022-03-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000658725	SCV003811686	uncertain significance	not provided	2023-05-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230444	SCV003929298	uncertain significance	not specified	2024-08-07	criteria provided, single submitter	clinical testing	Variant summary: POLG c.1402A>G (p.Asn468Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251488 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders, allowing no conclusion about variant significance. c.1402A>G has been reported in the literature in individuals affected with variety of POLG-related phenotypes. The variant has been reported in three affected family members (and no unaffected family members) with progressive external ophthalmoplegia and parkinsonism as well as a patient with early onset Parkinson's disease, all with a second variant of unknown significance (Luoma_2004, Ylonen_2017). Additionally, the variant was reported along with a pathogenic variant in cases of progressive external ophthalmoplegia and tetraparesis and mitochondrial neurogastrointestinal encephalopathy (Gonzalez-Vioque_2006, Woodbridge_2013). The variant has also been reported in the homozygous state in a patient with congenital ataxia who had no features suggestive of a POLG-related phenotype, therefore ITPR1 variants were considered resposible for congenital ataxia in this patient (Valence_2019). 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: 31658717, 16401742, 15351195, 15181170, 22647225, 29029963, 29997391). ClinVar contains an entry for this variant (Variation ID: 206596). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000658725	SCV004026046	uncertain significance	not provided	2022-05-20	criteria provided, single submitter	clinical testing	PM3
Baylor Genetics	RCV000470781	SCV004205841	likely pathogenic	Progressive sclerosing poliodystrophy	2024-03-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786516	SCV005398458	uncertain significance	Mitochondrial disease	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Variants in the centre of motif B in the polymerase domain (highly conserved active site), result in dominant disease (PMID: 28480171). (N) 0200 - Variant is predicted to result in a missense amino acid change from an asparagine to an aspartate (exon 7). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (138 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (6 heterozygotes, 0 homozygotes). (N) 0504 - Same amino acid change has been observed in mammals. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. It has been reported as compound heterozygous with another variant in patients with progressive external ophthalmoplegia. However, it has been classified as both pathogenic and VUS in ClinVar (PMID: 22647225, 16401742). (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678827	SCV000805013	uncertain significance	Lennox-Gastaut syndrome	2016-12-05	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000658725	SCV001952043	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000658725	SCV001968418	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004725036	SCV005335971	likely pathogenic	POLG-related disorder	2024-05-30	no assertion criteria provided	clinical testing	The POLG c.1402A>G variant is predicted to result in the amino acid substitution p.Asn468Asp. This variant has been reported in individuals with autosomal recessive POLG-related mitochondrial disease (Palin et al. 2013. PubMed ID: 23811324; Luoma et al. 2004. PubMed ID: 15351195; Woodbridge et al. 2013. PubMed ID: 22647225; González-Vioque et al. 2006. PubMed ID: 16401742; Buzkova et al. 2018. PubMed ID: 30373890). Some POLG variants have also been implicated in autosomal dominant progressive external ophthalmoplegia (PEO), and several PEO patients have been reported to carry this variant in the heterozygous state (Schulte et al. 2009. PubMed ID: 19752458). However, in a second family, heterozygous carriers of the c.1402A>G (p.Asn468Asp) variant were reportedly asymptomatic (Luoma et al. 2004. PubMed ID: 15351195). In ClinVar, this variant has conflicting interpretations of uncertain, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/206596/). This variant is reported in 0.072% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic for autosomal recessive disease.