Submissions for variant NM_004369.4(COL6A3):c.8189C>A (p.Ala2730Asp)

gnomAD frequency: 0.00110  dbSNP: rs138466455

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177942	SCV000229904	uncertain significance	not provided	2018-08-29	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000177942	SCV000281286	uncertain significance	not provided	2015-12-23	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV000254307	SCV000310233	uncertain significance	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000270502	SCV000428725	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.
GeneDx	RCV000177942	SCV000523314	uncertain significance	not provided	2023-06-23	criteria provided, single submitter	clinical testing	Reported as a variant of uncertain significance in multiple patients with limb-girdle muscular dystrophy (Nallamilli et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30564623)
Athena Diagnostics	RCV000254307	SCV000613017	likely benign	not specified	2021-03-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081264	SCV000657422	likely benign	Bethlem myopathy 1A	2024-01-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000177942	SCV001714680	uncertain significance	not provided	2019-06-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000177942	SCV001746699	uncertain significance	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254307	SCV005039064	uncertain significance	not specified	2024-03-26	criteria provided, single submitter	clinical testing	Variant summary: COL6A3 c.8189C>A (p.Ala2730Asp) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 1614142 control chromosomes in the gnomAD database, including 3 homozygotes. c.8189C>A has been reported in the literature as a VUS in settings of multigene panel testing on a cohort of individuals with clinically suspected of limb girdle muscular dystrophy (e.g., Nallamilli_2018). However, these report(s) do not provide unequivocal conclusions about association of the variant with Ullrich Congenital Muscular Dystrophy 1C/Bethlem myopathy or Dystonia 27 in the spectrum of COL6A3-related disorder spectrum. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 197034). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000177942	SCV001799403	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000177942	SCV001808285	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000177942	SCV001970637	uncertain significance	not provided		no assertion criteria provided	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002226459	SCV002505517	likely pathogenic	Tip-toe gait	2021-09-08	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.