ClinVar Miner

Submissions for variant NM_001849.4(COL6A2):c.736-2A>G

dbSNP: rs1057518925
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000415423 SCV000492938 likely pathogenic Muscular dystrophy; Limb-girdle muscle weakness; Hyperextensible hand joints; Fatigue 2014-11-17 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000733636 SCV000861725 pathogenic not provided 2018-06-12 criteria provided, single submitter clinical testing
3billion RCV001775116 SCV002012145 pathogenic Ullrich congenital muscular dystrophy 1A 2021-10-02 criteria provided, single submitter clinical testing Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as pathogenic (ClinVar ID: VCV000523809.3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV003517189 SCV004298811 pathogenic Bethlem myopathy 1A 2023-06-24 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 33537799). ClinVar contains an entry for this variant (Variation ID: 374143). Disruption of this splice site has been observed in individual(s) with autosomal dominant COL6A2-related conditions (PMID: 24801232, 25535305, 33537799). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 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 disease-causing for autosomal recessive COL6A2-related conditions (PMID: 21280092, 20976770). However, certain variants affecting donor or acceptor splice sites in the triple helical domain of COL6A2 are expected to result in in-frame exon skipping and have been reported to cause autosomal dominant COL6A2-related conditions (PMID: 18366090).

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