Submissions for variant NM_002693.3(POLG):c.926G>A (p.Arg309His)

gnomAD frequency: 0.00001  dbSNP: rs780953863

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000421279	SCV000520840	pathogenic	not provided	2024-10-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect resulting in mtDNA instability (PMID: 20601675); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30029678, 32169601, 36658419, 30843307, 37091313, 20601675, 27475922, 16621917, 28130605)
CeGaT Center for Human Genetics Tuebingen	RCV000421279	SCV001149573	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	POLG: PM3:Very Strong, PM1, PM2, PM5
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000421279	SCV001446708	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000421279	SCV002019468	pathogenic	not provided	2021-06-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861504	SCV002242087	pathogenic	Progressive sclerosing poliodystrophy	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 309 of the POLG protein (p.Arg309His). This variant is present in population databases (rs780953863, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal recessive POLG-related disease (PMID: 16621917, 30843307). 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: 381521). 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. Experimental studies have shown that this missense change affects POLG function (PMID: 20601675). This variant disrupts the p.Arg309 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26077851, 26169155). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001861504	SCV004205901	pathogenic	Progressive sclerosing poliodystrophy	2024-03-09	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV000421279	SCV001190063	uncertain significance	not provided		no assertion criteria provided	provider interpretation
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319987	SCV004023416	likely pathogenic	Tip-toe gait	2020-11-16	flagged submission	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.