ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1399G>A (p.Ala467Thr) (rs113994095)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720159 SCV000851036 pathogenic Seizures 2016-06-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function by in vitro/ex vivo assay,Other strong data supporting pathogenic classification
Athena Diagnostics Inc RCV000188658 SCV000614701 pathogenic not provided 2015-09-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188658 SCV000493450 likely pathogenic not provided 2016-07-31 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000184011 SCV000236534 pathogenic Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1 2013-12-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188658 SCV000331833 pathogenic not provided 2017-12-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515354 SCV000611297 pathogenic Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1 (MNGIE type); Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Cerebellar ataxia infantile with progressive external ophthalmoplegia; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000188658 SCV000242281 pathogenic not provided 2018-11-05 criteria provided, single submitter clinical testing The A467T variant is the most common variant in the POLG gene and accounts for 31% of disease-causing alleles (Tang et al., 2011). A467T was initially identified in individuals with autosomal recessive progressive external ophthalmoplegia (arPEO) and has subsequently been identified in patients with Alpers syndrome, sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), and other POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, and/or myopathy (vanGoethem et al., 2001). A467T alters a highly conserved position in the linker region of the polymerase, and functional studies indicate it significantly impairs the enzyme's catalytic activity and interferes with binding to the accessory subunit (Chan et al., 2005).
GeneReviews RCV000014440 SCV000040905 pathologic Cerebellar ataxia infantile with progressive external ophthalmoplegia 2012-10-11 no assertion criteria provided curation Converted during submission to Pathogenic.
GenomeConnect, ClinGen RCV000709980 SCV000840346 not provided POLG- Related Disorders no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Illumina Clinical Services Laboratory,Illumina RCV000347876 SCV000394291 pathogenic POLG-Related Spectrum Disorders 2016-06-14 criteria provided, single submitter clinical testing The c.1399G>A (p.Ala467Thr) variant is well described in the literature as one of the most common mutations associated with POLG-related disorders, particularly Alpert-Huttenlocher syndrome (Chan et al. 2005; Cohen et al. 2014; Rajakulendran et al. 2016). Across a selection of the literature, the p.Ala467Thr variant has been identified in at least 52 patients including 15 in a homozygous state and 37 in a compound heterozygous state (van Goethem et al. 2001; Tzoulis et al. 2006; Tang et al. 2011; Uusimaa et al. 2013; Rajakulendran et al. 2016). In addition the variant has been found in 154 out of 498 patient alleles (31%) (Tang et al. 2011). The p.Ala467Thr variant was found in three out of 229 controls in one study and is reported at a frequency of 0.001400 in the European American population of the Exome Sequencing Project. Functional studies have demonstrated that the p.Ala467Thr variant results in a drastically reduced polymerase gamma activity to 4 - 18% of the wild type, reduced DNA binding capability to 14% of the control value, and a reduction in a processivity due to an impaired interaction with the accessory subunit of the enzyme which then slows the rate of DNA synthesis (Chan et al. 2005; Luoma et al. 2005). Based on the collective evidence the p.Ala467Thr variant is classified as pathogenic for POLG-Related Disorders.
Invitae RCV000014443 SCV000630094 pathogenic Progressive sclerosing poliodystrophy 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 467 of the POLG protein (p.Ala467Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs113994095, ExAC 0.08%). This variant has been reported to be one of the most common mutations associated with autosomal recessive POLG-related disorders. It has been reported to segregate in several families and individuals affected with Alpers-Huttenlocher syndrome, autosomal recessive progressive external ophthalmoplegia, sensory ataxic neuropathy, dysarthria and ophthalmoplegia (SANDO), and other POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, and myopathy (PMID: 11431686, 26735972, 15122711, 25286830, 20691285,15917273). ClinVar contains an entry for this variant (Variation ID: 13496). Experimental studies have shown that this missense change results in decreased activity, DNA binding and processivity of the polymerase (PMID: 15917273, 16024923). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000014440 SCV000245651 pathogenic Cerebellar ataxia infantile with progressive external ophthalmoplegia 2014-04-24 criteria provided, single submitter clinical testing The Ala467Thr variant in POLG has been reported in >20 individuals with mitochondrial disease in both the homozygous and compound heterozygous states, with symptoms ranging from progressive external ophthalmoplegia to intractable epilepsy to Alpers syndrome (van Goethem 2001, van Goethem 2004, Ferrari 2005, Winterthun 2005, Lax 2012, Scalais 2012, Uusimaa 2012). This variant has also been identified in 0.14% (12/8598) of European American chromosomes and 0.09% (4/4400) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/. In vitro functional studies have shown that the Ala467Thr variant leads to loss of wild-type activity and binding affinity (Chan 2005, Luoma 2005). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000188658 SCV000802092 pathogenic not provided 2016-02-29 no assertion criteria provided clinical testing
OMIM RCV000014440 SCV000034690 pathogenic Cerebellar ataxia infantile with progressive external ophthalmoplegia 2011-02-11 no assertion criteria provided literature only
OMIM RCV000014441 SCV000034691 pathogenic Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis 2011-02-11 no assertion criteria provided literature only
OMIM RCV000014442 SCV000034692 pathogenic Myoclonic epilepsy myopathy sensory ataxia 2011-02-11 no assertion criteria provided literature only
OMIM RCV000014443 SCV000034693 pathogenic Progressive sclerosing poliodystrophy 2011-02-11 no assertion criteria provided literature only
Undiagnosed Diseases Network,NIH RCV000014443 SCV000837702 pathogenic Progressive sclerosing poliodystrophy 2018-01-03 criteria provided, single submitter clinical testing This is the most common pathogenic variant described in cases of Alpers-Huttenlocher syndrome (Mitochondrial DNA depletion syndrome 4A (Alpers type), MIM 203700), we have sparse records on the patient's phenotype (long deceased), but it seems a very reasonable clinical fit, albeit perhaps somewhat late onset (age 11).
Undiagnosed Diseases Network,NIH RCV000735201 SCV000863407 pathogenic POLG-related condition 2018-06-27 criteria provided, single submitter clinical testing Submitting this as a novel interpretation as this patient's phenotype does not fit any of the POLG-associated conditions listed in OMIM. This is a different observation than SCV000837701.1 where we observed this variant in a compound heterozygous state with another POLG variant and the patient fit the POLG-related conditions listed in OMIM.
Wellcome Centre for Mitochondrial Research,Newcastle University RCV000508942 SCV000575914 pathogenic Mitochondrial diseases 2017-04-07 no assertion criteria provided clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000014443 SCV000886901 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1399G>A (NP_002684.1:p.Ala467Thr) [GRCH38: NC_000015.10:g.89327201C>T] 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. PS3:Well established functional studies show a deleterious effect on POLG. PS4:Prevalence of variant in affecteds statistically increased over controls. 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. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.

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