Submissions for variant NM_002693.3(POLG):c.2794C>T (p.His932Tyr)

dbSNP: rs121918048

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758263	SCV000886911	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2794C>T (NP_002684.1:p.His932Tyr) [GRCH38: NC_000015.10:g.89320953G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:14635118 . 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. 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.
GeneDx	RCV001797046	SCV002038779	pathogenic	not provided	2023-05-03	criteria provided, single submitter	clinical testing	Published functional studies show that the equivalent yeast mutation to H932Y increased mtDNA instability, thus demonstrating a damaging effect (Baruffini et al., 2007); 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: 20837862, 14635118, 14745080, 21880868, 17980715, 29358615, 20220442, 36157077, 27535533)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758263	SCV004354156	pathogenic	Progressive sclerosing poliodystrophy	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 932 of the POLG protein (p.His932Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with POLG-related conditions (PMID: 14745080, 20837862, 29358615). 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: 13500). 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%. Experimental studies have shown that this missense change affects POLG function (PMID: 17980715). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700232	SCV005204261	pathogenic	Mitochondrial DNA depletion syndrome	2024-06-13	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2794C>T (p.His932Tyr) results in a conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250848 control chromosomes. c.2794C>T has been reported in the literature in the compound heterozygous state in multiple individuals affected with POLG-related conditions (e.g. Castiglioni_2018, DiFonzo_2003, Mancuso_2004, Tang_2011) and segregated with disease in at least one family (e.g. Mancuso_2004). These data indicate that the variant is very likely to be associated with disease. At least one in vitro study in yeast reports experimental evidence evaluating an impact on protein function (e.g. Baruffini_2010). This variant is also known as c.3076C>T. The following publications have been ascertained in the context of this evaluation (PMID: 17980715, 29358615, 14635118, 20837862, 14745080, 21880868). ClinVar contains an entry for this variant (Variation ID: 13500). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786259	SCV005399177	pathogenic	Mitochondrial disease	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, 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 mitochondrial disorder. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to tyrosine. (I) 0251 – This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in an annotated domain or motif (DNA polymerase family A domain; NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in patients with POLG-related mitochondrial disorder (ClinVar, PMID: 20837862, 21880868, 29358615). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant reduces the kinetic efficiency governing correct nucleotide incorporation (PMID:20685647). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005007844	SCV005633384	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	2024-06-14	criteria provided, single submitter	clinical testing
OMIM	RCV000014454	SCV000034704	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2004-01-27	no assertion criteria provided	literature only