Submissions for variant NM_004369.4(COL6A3):c.7258C>T (p.Arg2420Trp)

gnomAD frequency: 0.00131  dbSNP: rs150165484

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000657932	SCV000112895	uncertain significance	not provided	2017-03-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000282178	SCV000428751	benign	Collagen 6-related myopathy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000987061	SCV000657393	likely benign	Bethlem myopathy 1A	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000657932	SCV000779701	likely benign	not provided	2021-03-08	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in published literature in the heterozygous state, identified via direct sequencing of COL6A3 in a 63 year old individual with focal dystonia (Zech et al., 2015); This variant is associated with the following publications: (PMID: 30564623, 29970176, 30467950, 26004199)
Mendelics	RCV000987061	SCV001136251	uncertain significance	Bethlem myopathy 1A	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000657932	SCV001153362	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000657932	SCV001714681	uncertain significance	not provided	2019-05-06	criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002051806	SCV002319187	likely pathogenic	Tip-toe gait	2022-03-25	criteria provided, single submitter	clinical testing	Our patients have a gait disorder in the form of a toe walking gait, 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). Myopathy patients (children to the age of 14) typically suffer from hypotrophic muscles and a stress tremor but no pes cavus (Pomarino et al. 2024). Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. 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.