Submissions for variant NM_002693.3(POLG):c.2897T>G (p.Leu966Arg)

gnomAD frequency: 0.00001  dbSNP: rs142347031

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413284	SCV000490737	pathogenic	not provided	2023-06-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 17426723, 21824913, 23448099, 16545482, 22000311, 21704543, 18487244, 25525159, 30167885, 34690748, 32033288)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821077	SCV000961819	pathogenic	Progressive sclerosing poliodystrophy	2024-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 966 of the POLG protein (p.Leu966Arg). This variant is present in population databases (rs142347031, gnomAD 0.002%). This missense change has been observed in individual(s) with Alpers syndrome (PMID: 16545482, 17426723, 21704543, 22000311, 23448099; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.3179T>G. ClinVar contains an entry for this variant (Variation ID: 372473). 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.
Athena Diagnostics	RCV000413284	SCV001879834	likely pathogenic	not provided	2020-10-23	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 is statistically more frequent in affected individuals than in the general population and/or healthy controls. Computational tools predict that this variant is damaging.
Revvity Omics, Revvity	RCV000413284	SCV003813248	likely pathogenic	not provided	2023-05-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000821077	SCV004205889	pathogenic	Progressive sclerosing poliodystrophy	2023-11-17	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000821077	SCV004812699	pathogenic	Progressive sclerosing poliodystrophy	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in POLG is predicted to replace leucine with arginine at codon 966, p.(Leu966Arg). The leucine residue is highly conserved (100 vertebrates, UCSC), and is located in POLAc domain. There is a large physicochemical difference between leucine and arginine. The highest population minor allele frequency in gnomAD v2.1 is 0.003% (3/113,674 alleles) in European (non-Finnish) population, which is consistent with a recessive condition. This variant has been detected in at least six individuals with the POLG-related disorder Alpers-Huttenlocher syndrome. All these individuals were compound heterozygous for the variant and a pathogenic variant, and three of those were confirmed in trans (PMID: 16545482, 17426723, 18487244, 21704543, 22000311, 23448099, 30167885). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2_Supporting, PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800399	SCV005423085	likely pathogenic	POLG-Related Spectrum Disorders	2024-10-07	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2897T>G (p.Leu966Arg) 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 1.2e-05 in 251202 control chromosomes. c.2897T>G has been reported in the literature in individuals affected with POLG-Related Spectrum Disorders (Ashley_2008, Hunter_2011, McCoy_2011, Nguyen_JH, Obrien_2014, Uusimaa_2013). These data indicate that the variant is likely to 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: 18487244, 22000311, 21704543, 16545482, 24986207, 23448099). ClinVar contains an entry for this variant (Variation ID: 372473). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005010308	SCV005633380	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	2024-02-09	criteria provided, single submitter	clinical testing