Submissions for variant NM_001849.4(COL6A2):c.511G>A (p.Gly171Arg)

gnomAD frequency: 0.00116  dbSNP: rs200710788

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725047	SCV000333499	uncertain significance	not provided	2018-05-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000329881	SCV000436635	likely benign	Myosclerosis	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000386454	SCV000436636	benign	Collagen 6-related myopathy	2018-01-12	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.
GeneDx	RCV000725047	SCV000568740	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Reported previously as a variant of uncertain significance in patients with clinically suspected limb-girdle muscular dystrophy; however, no further clinical or segregation information was provided (Nallamilli et al., 2018); 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: 24036952, 34803902, 30564623)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001257054	SCV000657209	likely benign	Bethlem myopathy 1A	2024-01-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725047	SCV001153584	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	COL6A2: BS1
Mayo Clinic Laboratories, Mayo Clinic	RCV000725047	SCV001713888	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing	BS1
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001257054	SCV001976898	uncertain significance	Bethlem myopathy 1A	2021-10-06	criteria provided, single submitter	clinical testing	PP2, PP3, BS2
PreventionGenetics, part of Exact Sciences	RCV000723333	SCV004114626	uncertain significance	COL6A2-related disorder	2023-02-08	criteria provided, single submitter	clinical testing	The COL6A2 c.511G>A variant is predicted to result in the amino acid substitution p.Gly171Arg. This variant has been previously observed in a large cohort of individuals with clinically suspected limb-girdle muscular dystrophy (Table S7, Nallamilli et al. 2018. PubMed ID: 30564623). This variant is reported in 0.23% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote (http://gnomad.broadinstitute.org/variant/21-47532288-G-A). This variant has conflicting interpretations of benign, likely benign, and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/282184/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000723333	SCV000854730	uncertain significance	COL6A2-related disorder	2018-07-18	no assertion criteria provided	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002227938	SCV002507279	likely pathogenic	Tip-toe gait		no assertion criteria provided	clinical testing	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.