Submissions for variant NM_001849.4(COL6A2):c.855+1G>A

dbSNP: rs1057517988

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414393	SCV000491290	pathogenic	not provided	2017-09-19	criteria provided, single submitter	clinical testing	The c.855+1G>A variant in the COL6A2 gene has been reported previously as a de novo heterozygous variant in one individual with moderately progressive collagen VI-related myopathy (Brinas et al., 2009). This splice site variant destroys the canonical splice donor site in intron 6. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.855+1G>A variant was not observed in approximately 6500 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.855+1G>A as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861417	SCV002238039	pathogenic	Bethlem myopathy 1A	2021-09-14	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with autosomal dominant Ullrich congenital muscular dystrophy (PMID: 24271325). In at least one individual the variant was observed to be de novo. This variant has been reported in individual(s) with autosomal recessive COL6A2-related muscular dystrophy (PMID: 32065942); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 372791). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 6 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 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.