Submissions for variant NM_002693.3(POLG):c.3573G>T (p.Lys1191Asn)

dbSNP: rs1085307741

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV001526408	SCV001736746	likely pathogenic	Mitochondrial disease	2021-05-06	reviewed by expert panel	curation	The c.3573G>T (p.K1191N) variant in POLG is absent in population databases (PM2). Computational prediction tool Revel score 0.876 (PP3 met - Revel score > 0.75). This variant has been seen in 3 cases in the compound heterozygote state: in two cases, with Ala467Thr presenting with Alpers syndrome, and one with c.752C>T (p.Thr251Ile) / c.1760 C>T (p.Pro587Leu) presenting with CPEO spectrum (PM3_strong met; PMID: 16621917; PMID: 21880868; PMID: 19538466). In summary, this variant is characterized as a likely pathogenic variant for primary mitochondrial disease inherited in an autosomal recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, PM3_strong, PP3.
GeneDx	RCV000489004	SCV000577194	likely pathogenic	not provided	2019-05-24	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: 30423451, 16621917, 21038416, 21880868, 19538466, 24508722)
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758421	SCV000887125	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3573G>T (NP_002684.1:p.Lys1191Asn) [GRCH38: NC_000015.10:g.89317446C>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16621917 . 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. 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.
PreventionGenetics, part of Exact Sciences	RCV003985792	SCV004104154	likely pathogenic	POLG-related disorder	2023-05-02	criteria provided, single submitter	clinical testing	The POLG c.3573G>T variant is predicted to result in the amino acid substitution p.Lys1191Asn. This variant has been reported in the compound heterozygous state with the pathogenic variant p.Ala467Thr or a pathogenic complex allele p.[Thr251Ile;Pro587Leu] in individuals with POLG-related disorders (Horvath et al. 2006. PubMed ID: 16621917; Müller-Höcker et al. 2011. PubMed ID: 19538466; Piekutowska-Abramczuk et al. 2018. PubMed ID: 30423451; Table S2, Kierdaszuk et al. 2021. PubMed ID: 33396418). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is classified as likely pathogenic by the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/426681/). We interpret this variant as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758421	SCV004297671	pathogenic	Progressive sclerosing poliodystrophy	2022-12-02	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 426681). This missense change has been observed in individual(s) with autosomal recessive POLG-related disorders (PMID: 16621917, 19538466, 30423451). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1191 of the POLG protein (p.Lys1191Asn). 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. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000489004	SCV005042235	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	POLG: PM3:Very Strong, PM2, PM5, PP3
Athena Diagnostics	RCV000489004	SCV005622459	likely pathogenic	not provided	2024-05-31	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with a POLG-related disorder. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 32234506)
Mayo Clinic Laboratories, Mayo Clinic	RCV000489004	SCV000802075	uncertain significance	not provided	2016-03-07	no assertion criteria provided	clinical testing