Submissions for variant NM_001849.4(COL6A2):c.1970-3C>A

gnomAD frequency: 0.00118  dbSNP: rs201879417

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000415855	SCV000111749	uncertain significance	not provided	2018-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000415855	SCV000196783	uncertain significance	not provided	2022-09-19	criteria provided, single submitter	clinical testing	Identified in two patients with Bethlem myopathy (Lampe et al., 2005; Tagliavini et al., 2014); however, functional characterization of the variant was not performed; Identified in five patients with limb-girdle muscular dystrophy type 1A who were heterozygous for this variant and did not have a second COL6A2 variant (Nallamilli et al., 2018); however, information regarding parental testing was not provided; Reported previously as a variant of uncertain significance in a patient with progressive muscle weakness in all extremities, who also had a pathogenic variant in the VCP gene and received a diagnosis of VCP myopathy (Bazrafshan et al., 2021); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 15689448, 24907562, 27656840, 30564623, 33567613)
Illumina Laboratory Services, Illumina	RCV000259240	SCV000436731	likely benign	Myosclerosis	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000300588	SCV000436732	likely benign	Collagen 6-related myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000415855	SCV000493224	uncertain significance	not provided	2016-09-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084118	SCV000657127	likely benign	Bethlem myopathy 1A	2025-01-06	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000709829	SCV000840158	not provided	Bethlem myopathy 1A; Ullrich congenital muscular dystrophy 1A		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319318	SCV004023357	likely pathogenic	Tip-toe gait	2022-02-14	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.