ClinVar Miner

Submissions for variant NM_001849.4(COL6A2):c.1572+1G>A

dbSNP: rs1057520717
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000423788 SCV000517073 pathogenic not provided 2015-05-11 criteria provided, single submitter clinical testing The c.1572+1 G>A splice site variant in the COL6A2 gene destroys the canonical splice donor site inintron 19. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that issubject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used forprotein translation. It was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variantin these populations. Additionally, another splicing variant affecting the same canonical donor site inintron 19 (c.1572+1 G>C) has been published in association with a COL6A2-related disorder (Okada et al.,2007). Although c.1572+1 G>A has not been previously reported to our knowledge, it is expected to be apathogenic variant.
Revvity Omics, Revvity RCV000423788 SCV002023336 likely pathogenic not provided 2021-03-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001851051 SCV002134689 pathogenic Bethlem myopathy 1A 2023-07-18 criteria provided, single submitter clinical testing Disruption of this splice site has been observed in individuals with autosomal recessive COL6A2-related conditions (PMID: 17785673; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 19 of the COL6A2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL6A2 are known to be pathogenic (PMID: 19884007, 20976770). ClinVar contains an entry for this variant (Variation ID: 379733). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Neuberg Centre For Genomic Medicine, NCGM RCV001851051 SCV004047968 pathogenic Bethlem myopathy 1A criteria provided, single submitter clinical testing The splice donor COL6A2 (c.1572+1G>A) variant has been reported individuals affected with Bethlem myopathy 1 (Foley et. al., 2009). The c.1572+1G>A variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (Baralle et. al., 2005), and loss-of-function variants in COL6A2 are known to be pathogenic (Foley et. al., 2009). For these reasons, this variant has been classified as Pathogenic

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