chr15-89323460-C-G

Variant names:

• chr15-89323460-C-G
• rs121918054
• NM_002693.3:c.2209G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1_Moderate PP5_Very_Strong

The NM_002693.3(POLG):​c.2209G>C​(p.Gly737Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00162 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (1 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:34 U:1
• Conservation: PhyloP100: 6.01
• Publications: 40 publications found

Genes affected

POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

POLG Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial DNA depletion syndrome 4a

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive mitochondrial ataxia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia with epilepsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_002693.3 (POLG) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP5: Variant 15-89323460-C-G is Pathogenic according to our data. Variant chr15-89323460-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.2209G>C	p.Gly737Arg	missense_variant	Exon 13 of 23	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.2209G>C	p.Gly737Arg	missense_variant	Exon 13 of 23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.2209G>C	p.Gly737Arg	missense_variant	Exon 13 of 23	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.000913 AC: 139 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000688 AC: 173 AN: 251378 AF XY: 0.000699

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00169 AC: 2474 AN: 1461750 Hom.: 1 Cov.: 31 AF XY: 0.00160 AC XY: 1163 AN XY: 727194

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00206 AC: 2285 AN: 1111882

Other (OTH) AF: 0.00257 AC: 155 AN: 60394

GnomAD4 genome AF: 0.000913 AC: 139 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74480

African (AFR) AF: 0.000505 AC: 21 AN: 41576

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00160 AC: 109 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.000937

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.000684 AC: 83

EpiCase AF: 0.00180

EpiControl AF: 0.00130

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:34 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10 Uncertain:1

Jul 11, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (PMID: 18546365, 21880868). This variant has been identified in multiple unrelated individuals with autosomal recessive POLG-related disorders and appears to segregate with disease in at least one family. Affected heterozygous individuals have also been reported. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -

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Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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Jan 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Sep 16, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLG c.2209G>C; p.Gly737Arg variant (rs121918054) is reported in the literature in multiple individuals with symptoms or diagnoses of a POLG-associated disorder, including mitochondrial DNA depletion syndrome, progressive external ophthalmoplegia, early-onset parkinsonism, and sensorimotor neuropathy (Davidzon 2006, Harrower 2008, Horvath 2006, Milone 2008, Tzoulis 2009, Wong 2008). Multiple affected individuals also carried a second pathogenic variant, with parental testing confirming compound heterozygosity of several probands (Davidzon 2006, Harrower 2008, Horvath 2006, Milone 2008, Tzoulis 2009, Wong 2008). Additionally, the p.Gly737Arg variant was reported to co-segregate with autosomal recessive disease in at least two families (Davidzon 2006, Harrower 2008). This variant is found in the non-Finnish European population with an overall allele frequency of 0.13% (171/129104 alleles) in the Genome Aggregation Database. The glycine at codon 737 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Bereau M et al. The wide POLG-related spectrum: An integrated view. J Neurol Sci. 2016 Sep 15;368:70-6. Davidzon G et al. Early-onset familial parkinsonism due to POLG mutations. Ann Neurol. 2006 May;59(5):859-62. Harrower T et al. POLG1 mutations manifesting as autosomal recessive axonal Charcot-Marie-Tooth disease. Arch Neurol. 2008 Jan;65(1):133-6. Horvath R et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain. 2006 Jul;129(Pt 7):1674-84. Milone M et al. Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations. Neuromuscul Disord. 2008 Aug;18(8):626-32. Stumpf JD et al. Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb Perspect Biol. 2013 Apr 1;5(4):a011395. Tzoulis C et al. Mitochondrial DNA depletion in progressive external ophthalmoplegia caused by POLG1 mutations. Acta Neurol Scand Suppl. 2009;(189):38-41. Wong LJ et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat. 2008 Sep;29(9):E150-72. -

Nov 08, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PM3, PS4_moderate -

Feb 10, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16634032, 24725338, 18546365, 25356970, 30609409, 31521625, 16621917, 21880868, 19566497, 27185166, 27016405, 27349602, 28812649, 29655203, 30843307, 31731261, 31980526, 34062649, 33300680, 33726816) -

Jul 13, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLG: PM3:Very Strong, PM2:Supporting, PP3 -

Progressive sclerosing poliodystrophy Pathogenic:8

Oct 01, 2018

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_002693.2:c.2209G>C (NP_002684.1:p.Gly737Arg) [GRCH38: NC_000015.10:g.89323460C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. 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. 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. -

Jun 21, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Dec 16, 2020

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLG c.2209G>C variant is classified as Likely Pathogenic (PS4_Moderate, PM3_Strong, PP3, PP5) -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 737 of the POLG protein (p.Gly737Arg). This variant is present in population databases (rs121918054, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 16634032, 18546365, 18585914, 19566497, 24725338). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13513). 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. -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Mar 21, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (G>C) at coding position 2209 of the POLG gene that results in a glycine to arginine amino acid change at residue 737 of the POLG protein. The Gly737 residue falls in the linker region (PMID: 21824913) which plays a critical role in replicating the mitochondrial genome. This is a previously reported variant (ClinVar) that has been observed in individuals affected by a variety of phenotypes when in the compound heterozygous state (PMID: 33791913). These phenotypes include, but are not limited to, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), myocerebrohepatopathy spectrum disorder, progressive exterl ophthalmoplegia, Charcot-Marie-Tooth disease, hearing loss, cerebellar atrophy, epilepsy, dystonia, developmental delay, dysmorphic features, congenital cataract, and rel tubulopathy (PMID: 18546365, 18585914, 16621917, 19566497, 18195151, 30843307, 34062649). This variant is present in 211 of 282,774 (0.07%) alleles in the gnomAD population database. Multiple bioinformatic tools predict that this glycine to arginine amino acid change would be damaging, and the glycine residue at this position is highly conserved across the vertebrate species examined. In addition, studies of cultured fibroblasts derived from compound heterozygous affected individuals exhibited a reduced mtD replication rate (PMID: 21138766, 24725338). Given this information, we consider this a likely pathogenic variant. ACMG Criteria: PM3, PP2, PP3, PS3 -

Jul 29, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POLG-Related Spectrum Disorders Pathogenic:3

May 31, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLG c.2209G>C (p.Gly737Arg) results in a non-conservative amino acid change located in the linker region (Wong_2008) 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 0.00069 in 251378 control chromosomes. c.2209G>C has been reported in the literature in multiple individuals affected with POLG-Related Spectrum Disorders (example, Davidzon_2006, Milone_2008, Wong_2008, Tzoulis_2009, Stewart_2011, Sitarz_2014, Phillips_2019, Bychkov_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly737Arg (NM_002693.2 c.2209G>C) variant in POLG has been reported in 10 compound heterozygous individuals presenting with POLG-related mitochondrial DNA (mtDNA) depletion syndromes (Horvath 2006, Davidzon 2006, Wong 2008, Harrower 2 008, Tzoulis 2009, Tang 2011). This variant has been identified in 0.1% (67/6651 4) of European chromosomes in ExAC though this frequency in consistent with a re cessive carrier frequency. In summary, although additional studies are required to fully establish its clinical significance, the p. Gly737Arg variant is likely pathogenic for POLG-related mitochondrial DNA (mtDNA) depletion syndromes in an autosomal recessive manner based upon biallelic case observations and consisten t allele frequency. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:2

Sep 16, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:2

Apr 07, 2017

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with POLG-related disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants are usually inherited in a recessive manner, however progressive external ophthalmoplegia can also be dominant when heterozygous variants are located in the highly conserved active site of motif B of the polymerase domain (PMID: 30451971). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 303 heterozygotes, 0 homozygotes). In addition, a different nucleotide change (c.2209G>A) resulting in the same residue is present in gnomAD (v2: 1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as pathogenic in many compound heterozygous individuals with POLG-related disorders (ClinVar, PMID: 16634032, 21880868, 30843307). In addition, this variant has been reported in three heterozygous patients with a phenotype consistent with POLG-related mitochondrial disease, however a second hit was not identified and the possibility of autosomal recessive disease was not excluded (PMID: 18546365). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) -

POLG-related disorder Pathogenic:2

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1, PS3, PM2, PM3, PP1, PP4 -

Sep 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLG c.2209G>C variant is predicted to result in the amino acid substitution p.Gly737Arg. This variant has been reported along with a second POLG variant in several individuals with mitochondrial DNA maintenance disorders which include progressive external opthalmoplegia, Charcot-Marie-Tooth Disease, and early-onset Parkinsonism; this variant was reported to co-segregate with autosomal recessive disease in at least two families (see, for example, Davidzon et al. 2006. PubMed ID: 16634032; Harrower et al. 2008. PubMed ID: 18195151; supplementary data, Tang et al, 2011. PMID: 21880868). This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common to be a cause of autosomal dominant disease. This variant has been interpreted as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13513). Given all the evidence, we interpret c.2209G>C (p.Gly737Arg) as likely pathogenic for autosomal recessive POLG-related disorders. -

Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:2

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLG NM_002693 exon 13 p.Gly737Arg (c.2209G>C): This variant has been reported in the literature in several individuals with various presentations of POLG-related disease (neuropathy, seizures, chronic progressive external opthalmoplegia (CPEO), ptosis, myopathy or early parkinsonism) as compound heterozygotes, segregating with disease in at least 1 affected family member (Davidzon 2006 PMID:16634032, Horvath 2006 PMID:16621917, Harrower 2008 PMID:18195151, Wong 2008 PMID:18546365, Tzoulis 2009 PMID:19566497, Tang 2011 PMID:21880868, Sitarz 2014 PMID:247253378, Rempe 2016 PMID:27185166). This variant has also been reported as heterozygous in at least 3 individuals with POLG-related presentations, as well as in 1 individual with Charcot-Marie-Tooth disease Type 2, segregating with disease in 1 sibling (Harrower 2008 PMID:18195151, Wong 2008 PMID:18546365). This variant is present in 0.1% (162/126642) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121918054). This variant is present in ClinVar with several entries, though the interpretation among labs is inconsistent (Variation ID:13513). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but the high presence of this variant in the general population, variable clinical presentation in reported individuals and inconsistent community consensus interpretation of this variant suggests that further evidence for pathogenicity is required. Therefore, this variant classified as likely pathogenic. -

Inborn genetic diseases Pathogenic:1

Nov 17, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2209G>C (p.G737R) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 2209, causing the glycine (G) at amino acid position 737 to be replaced by an arginine (R). for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant POLG-related progressive external ophthalmoplegia is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.07% (211/282774) total alleles studied. The highest observed frequency was 0.13% (171/129104) of European (non-Finnish) alleles. This is a well described common POLG mutation, having been detected with a frequency of close to 4% of alleles in affected individuals. In several studies, it has been detected in the compound heterozygous state in individuals exhibiting a wide range of phenotypes: from adult onset muscle weakness, myopathy, neuropathy, and ataxia, to early onset liver failure, seizures, and childhood death (Davidzon, 2006; Horvath, 2006; Harrower, 2008; Milone, 2008; Tzoulis, 2009; Tang, 2011; Rempe, 2016; Farwell, 2015; Phillips, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Pathogenic:1

Dec 22, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_Strong, PP1, PP3 -

Hereditary spastic paraplegia Pathogenic:1

Dec 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Tip-toe gait Pathogenic:1

Jan 10, 2023

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:1

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Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		6.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.86		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);
MVP		0.98
MPC		0.72
ClinPred		0.12	T
GERP RS		5.6
Varity_R		0.64
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121918054; hg19: chr15-89866691; COSMIC: COSV104571417; COSMIC: COSV104571417;