Submissions for variant NM_002693.3(POLG):c.3527C>T (p.Ser1176Leu)

gnomAD frequency: 0.00001  dbSNP: rs776031396

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493365	SCV000583174	likely pathogenic	not provided	2021-01-29	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12210792, 15913923, 15349879, 32347949)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686358	SCV000813874	pathogenic	Progressive sclerosing poliodystrophy	2024-03-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1176 of the POLG protein (p.Ser1176Leu). This variant is present in population databases (rs776031396, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive progressive external ophthalmoplegia (PMID: 12210792, 15349879). 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: 430382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375606	SCV001572514	likely pathogenic	POLG-Related Spectrum Disorders	2021-04-08	criteria provided, single submitter	clinical testing	Variant summary: POLG c.3527C>T (p.Ser1176Leu) results in a non-conservative amino acid change located in the 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 8e-06 in 251486 control chromosomes (gnomAD). The variant, c.3527C>T, has been reported in the literature in a single family, with four compound heterozygous individuals affected with autosomal recessive progressive external ophthalmoplegia (Lamantea_2002, Lamantea_2004). 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. Three submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=1) / likely pathogenic (n=1) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002524050	SCV003751618	likely pathogenic	Inborn genetic diseases	2022-02-28	criteria provided, single submitter	clinical testing	The c.3527C>T (p.S1176L) alteration is located in exon 22 (coding exon 21) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 3527, causing the serine (S) at amino acid position 1176 to be replaced by a leucine (L). Based on the available evidence, this variant is expected to be causative of autosomal recessive POLG-related mitochondrial disorders when present along with a second pathogenic or likely pathogenic variant on the other allele; however, its clinical significance for autosomal dominant progressive external ophthalmoplegia is unclear. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (2/251486) total alleles studied. The highest observed frequency was <0.01% (2/113762) of European (non-Finnish) alleles. The p.S1176L variant was detected in trans with a second POLG variant and co-segregated with disease in one family with autosomal recessive progressive external ophthalmoplegia (Lamantea, 2002; Lamantea, 2004). 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 likely pathogenic.
Baylor Genetics	RCV000686358	SCV004205863	likely pathogenic	Progressive sclerosing poliodystrophy	2024-03-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760533	SCV005368061	uncertain significance	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	2024-04-24	criteria provided, single submitter	clinical testing	Criteria applied: PS4_SUP,PM2_SUP,PP3, PM2_SUP
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000493365	SCV001251868	uncertain significance	not provided	2020-05-03	flagged submission	clinical testing