Submissions for variant NM_002693.3(POLG):c.830A>T (p.His277Leu)

dbSNP: rs138929605

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188643	SCV000242266	likely pathogenic	not provided	2022-12-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25203713, 22000311, 21301859, 22357363, 27987238, 30609409, 24508722, 22114710, 28337550, 21880868, 26095671, 27538604, 24642831, 32347949, 18487244)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000188643	SCV000281184	uncertain significance	not provided	2017-10-05	criteria provided, single submitter	clinical testing
Invitae	RCV000231645	SCV000287676	pathogenic	Progressive sclerosing poliodystrophy	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 277 of the POLG protein (p.His277Leu). This variant is present in population databases (rs138929605, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 18487244, 21301859, 22357363). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 206583). 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 not expected to disrupt POLG protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POLG function (PMID: 22114710, 24508722, 26095671, 27987238). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000396333	SCV000394295	uncertain significance	POLG-Related Spectrum Disorders	2017-04-27	criteria provided, single submitter	clinical testing	The POLG c.830A>T (p.His277Leu) missense variant has been reported in two studies in which it is found in a compound heterozygous state in two patients (Ashley et al. 2008; Sato et al. 2011). The variant was absent from 50 controls, but is reported at a frequency of 0.00069 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.His277Leu variant had normal DNA binding affinity and was found to have similar exonuclease activity and DNA strand displacement activity in vitro as compared to wild type (Macao et al. 2015). The evidence for this variant is limited. The p.His277Leu variant is classified as a variant of unknown significance, but suspicious for pathogenicity for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000616176	SCV000712078	likely pathogenic	Mitochondrial DNA depletion syndrome	2016-05-15	criteria provided, single submitter	clinical testing	The p.His277Leu variant in POLG has been previously reported in one child with A lpers syndrome (Ashley 2008), one patient with progressive external ophthalmople gia and parkinsonism (Sato 2011), one patient with mitochondrial DNA depletion s yndrome presenting as sensory ataxic neuropathy with cerebellar features (McKelv ie 2012). All three patients were compound heterozygotes. This variant has been identified in 48/121174 of chromosomes by the Exome Aggregation Consortium (ExAC , http://exac.broadinstitute.org; dbSNP rs138929605). Although this variant has been seen in the general population, its frequency is low enough to be consisten t with a recessive carrier frequency. Computational prediction tools and conserv ation analysis do not provide strong support for or against an impact to the pro tein. In summary, although additional studies are required to fully establish it s clinical significance, the p.His277Leu variant is likely pathogenic.
Eurofins Ntd Llc (ga)	RCV000188643	SCV000855031	uncertain significance	not provided	2018-03-02	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000231645	SCV000886921	likely pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.830A>T (NP_002684.1:p.His277Leu) [GRCH38: NC_000015.10:g.89330106T>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18487244 . This variant meets the following evidence codes reported in the ACMG-guideline. 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 Likely Pathogenic.
Baylor Genetics	RCV001004406	SCV001163400	likely pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4b		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000188643	SCV001474653	likely benign	not provided	2020-04-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000188643	SCV001716243	uncertain significance	not provided	2020-07-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000188643	SCV001961536	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	POLG: PM3:Very Strong, PM2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847834	SCV002104889	uncertain significance	Hereditary spastic paraplegia	2019-11-01	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000188643	SCV002502899	likely pathogenic	not provided	2022-02-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002514036	SCV003714211	uncertain significance	Inborn genetic diseases	2021-03-26	criteria provided, single submitter	clinical testing	The c.830A>T (p.H277L) alteration is located in exon 3 (coding exon 2) of the POLG gene. This alteration results from a A to T substitution at nucleotide position 830, causing the histidine (H) at amino acid position 277 to be replaced by a leucine (L). The in silico prediction for the p.H277L alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000188643	SCV003811687	uncertain significance	not provided	2020-11-27	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000188643	SCV003932157	uncertain significance	not provided	2023-02-28	criteria provided, single submitter	clinical testing	PM3, PP1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235111	SCV003934843	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: POLG c.830A>T (p.His277Leu) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain (IPR041336) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 251244 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related and/or POLG-Related Spectrum Disorders (0.00038 vs 0.0035), allowing no conclusion about variant significance. c.830A>T has been reported in the literature as a compound heterozygous genotype in individuals affected with POLG-Related Spectrum Disorders, including Alpers syndrome and progressive external ophthalmoplegia (PEO) (e.g. Ashley_2008, Sato_2011, McKelvie_2012). It has also been reported in two individuals affected with infantile hepatopathy with a pathogenic variant in trans, but found also with another POLG variant (p. R232H) in cis (Hunter_2011). These data indicate that the variant may be associated with disease. Of note, POLG variants have been reported in association with autosomal recessive progressive external ophthalmoplegia; and Autosomal dominant progressive external ophthalmoplegia. Experimental evidence evaluating an impact on protein function showed no damaging effect of this variant in its ability to bind and synthesize DNA and in its exonuclease and strand displacement activity (Macao_2015). The following publications have been ascertained in the context of this evaluation (PMID: 18487244, 22000311, 33791913, 26095671, 35114397, 22357363, 30451971, 21301859). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV000231645	SCV004205845	likely pathogenic	Progressive sclerosing poliodystrophy	2024-03-30	criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002226693	SCV002505660	likely pathogenic	Tip-toe gait	2021-09-08	no assertion criteria provided	clinical testing	Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.