ClinVar Miner

Submissions for variant NM_001849.3(COL6A2):c.1970-9G>A (rs747900252)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000255313 SCV000613011 pathogenic not provided 2017-02-10 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000255313 SCV000609516 likely pathogenic not provided 2017-04-21 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626815 SCV000747518 pathogenic Muscle weakness; Difficulty walking; Falls; Hip flexor weakness; Dysplasia of acetabulum 2017-01-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255313 SCV000701241 pathogenic not provided 2018-07-10 criteria provided, single submitter clinical testing
GeneDx RCV000255313 SCV000322473 pathogenic not provided 2015-12-21 criteria provided, single submitter clinical testing The c.1970-9G>A pathogenic variant in the COL6A2 gene has been reported previously in the homozygous state in individuals with Ullrich congenital muscular dystrophy (Martoni et al., 2009; Sabatelli et al., 2011), and in the heterozygous state with another variant in an individual with Bethlem myopathy (Deconinck et al., 2014). Functional studies show this variant affects the deposition and organization of collagen VI in the extracellular matrix, and the collagen VI level is decreased (Martoni et al., 2009). The c.1970-9G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1970-9G>A as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000313321 SCV000436729 likely benign Myosclerosis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000354105 SCV000436730 pathogenic Collagen VI-related myopathy 2018-05-03 criteria provided, single submitter clinical testing The COL6A2 c.1970-9G>A splice region variant has been reported in at least six studies in which it was found in a total of seven affected individuals, including in one in a homozygous state, in five in a compound heterozygous state with a truncating variant on the second allele, and in one in a heterozygous state in whom the second allele was not detected. The individuals were affected with a range of phenotypes from a moderately severe form of Ullrich congenital muscular dystrophy through different intermediate phenotypes to a milder Bethlem myopathy (Martoni et al. 2009; Deconinck et al. 2010; Foley et al. 2011; Quijano-Roy et al. 2014; Deconinck et al. 2015; Stehlíková et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000436 in the Latino population of the Genome Aggregation Database. The c.1970-9G>A variant was shown to create a cryptic splice site in intron 25, leading to a frameshift and premature termination of the protein and reduced transcript levels to 20% of normal (Martoni et al. 2009). RT-PCR experiments in patient fibroblasts showed the presence of some normally spliced transcript (Foley e al. 2011). Studies in patient fibroblast cultures demonstrated that the variant resulted in significantly reduced levels of collagen VI protein, decreased intracellular secretion, and abnormal deposition and organization of the protein in the extracellular matrix (Martoni et al. 2009; Deconinck et al. 2015). Based on the collective evidence, the c.1970-9G>A variant is classified as pathogenic for an autosomal recessive form of collagen type VI-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000556474 SCV000657128 pathogenic Bethlem myopathy 1 2018-11-05 criteria provided, single submitter clinical testing This sequence change falls in intron 25 of the COL6A2 gene. It does not directly change the encoded amino acid sequence of the COL6A2 protein. This variant is present in population databases (rs747900252, ExAC 0.02%). This variant has been reported in the homozygous state in an individual affected with autosomal recessive Ullrich congenital muscular dystrophy (UCMD), and in the compound heterozygous state along with a second COL6A2 truncating variant in multiple individuals affected with autosomal recessive UCMD or Bethlem myopathy (BM) (PMID: 19309692, 21280092, 25535305, 20576434). ClinVar contains an entry for this variant (Variation ID: 265506). Truncating variants in COL6A2 are known to be pathogenic (PMID: 21280092, 20976770). Experimental studies have shown that this intronic change alters mRNA splicing by creating a cryptic acceptor splice site in intron 25, leading to a premature truncation codon, which results in overall reduced COL6A2 protein levels (PMID: 19309692). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844694 SCV000712168 pathogenic Qualitative or quantitative defects of collagen 6 2016-06-07 criteria provided, single submitter clinical testing The c.1970-9G>A variant in COL6A2 has been reported in 3 individuals (two compou nd heterozygotes who had other disease-causing variants in trans and one homozyg ote) with Ullrich congenital muscular dystrophy (Martoni 2009, Foley 2011, Decon ninck 2014). This variant has also been identified in 7/113354 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s747900252). This frequency is low enough to be consistent with a recessive carr ier frequency. The c.1970-9G>A variant was demonstrated to cause altered splici ng, leading to a frameshift and a truncated or absent protein (Martoni 2009, Fol ey 2011). In summary, this variant meets our criteria to be classified as patho genic for collagen VI-related myopathy in an autosomal recessive manner based up on its segregation in affected individuals, low frequency in controls and functi onal impact.

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