ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2890C>T (p.Arg964Cys) (rs201477273)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000718592 SCV000849456 likely pathogenic Seizures 2017-05-02 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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188591 SCV000344604 uncertain significance not provided 2017-10-09 criteria provided, single submitter clinical testing
GeneDx RCV000188591 SCV000242214 pathogenic not provided 2018-10-05 criteria provided, single submitter clinical testing The R964C pathogenic variant in the POLG gene has been reported in individuals with ataxia, neuropathy, epilepsy, and restless leg syndrome who had another variant on the other chromosome (Tang et al., 2011; Stricker et al., 2009). It was also reported in a 2 year old child with hypotonia and ataxia in whom a second POLG variant was not detected (Wong et al., 2008), and in an 8 year old child with hypotonia, ataxia, developmental delay, and cerebralatrophy/hypoplasia who had another POLG variant on the other chromosome (Ohba et al., 2013). The R964C variant is observed in 80/8646 (0.9%) alleles from individuals of East Asian background (Lek et al., 2016). R964C is located in the highly conserved carboxy-terminal polymerase (pol) domain, and R964C polymerase gamma showed reduced activity in vitro compared to wild-type polymerase gamma (Yamanaka et al., 2007; Bailey et al., 2009). Therefore, based on the currently available information, R964C is considered a pathogenic variant.
Invitae RCV000633558 SCV000754804 uncertain significance Progressive sclerosing poliodystrophy 2018-06-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 964 of the POLG protein (p.Arg964Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201477273, ExAC 0.9%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in combination with other POLG variants in individuals affected with progressive external ophthalmoplegia (PEO) and ataxia neuropathy spectrum, and epilepsy (PMID: 24091540, 18546365, 19762913) and as homozygous in an individual affected with lactic acidosis (PMID: 17436221). This variant has also been reported as heterozygous in individuals affected with ataxia, hypotonia, seizure, developmental delay, and PEO (PMID: 21880868, 18546365). ClinVar contains an entry for this variant (Variation ID: 206537). Experimental studies have shown that this missense change has reduced activity in vitro compared to wild-type polymerase gamma (PMID: 17436221, 19364868). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490261 SCV000267455 likely pathogenic Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2016-03-18 criteria provided, single submitter reference population
Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicine RCV000633558 SCV000887118 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2890C>T (NP_002684.1:p.Arg964Cys) [GRCH38: NC_000015.10:g.89320857G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17436221 . 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. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. 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.

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