Submissions for variant NM_001849.4(COL6A2):c.1770+1del

dbSNP: rs886044215

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519128	SCV000617759	likely pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19884007, 24077912)
Eurofins Ntd Llc (ga)	RCV000519128	SCV000701359	likely pathogenic	not provided	2016-07-25	criteria provided, single submitter	clinical testing
Invitae	RCV002519323	SCV002998485	pathogenic	Bethlem myopathy 1	2021-12-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 19884007). ClinVar contains an entry for this variant (Variation ID: 289581). This variant is also known as p.Thr590ThrfsX4 and c.1770+1del. This premature translational stop signal has been observed in individual(s) with autosomal recessive Bethlem myopathy (PMID: 19884007). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Glu591Serfs*5) in the COL6A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL6A2 are known to be pathogenic (PMID: 19884007, 20976770). This variant also falls at the last nucleotide of exon 23, which is part of the consensus splice site for this exon.
PreventionGenetics, part of Exact Sciences	RCV003940069	SCV004749636	pathogenic	COL6A2-related condition	2023-12-13	criteria provided, single submitter	clinical testing	The COL6A2 c.1770+1delG variant is predicted to result in a deletion affecting a canonical splice site. This variant has been reported in the compound heterozygous state in two siblings with Bethlem myopathy (Reported as c.1770delG in Foley et al 2009. PubMed ID: 19884007). One of the unaffected parents was heterozygous for the c.1770+1del variant, suggested this variant causes autosomal recessive COL6A2-related myopathy. RNA studies from one sibling indicated that the c.1770+1del results in skipping of exon 23. In addition, at PreventionGenetics we have observed this variant in the compound heterozygous state in another patient. In summary, the c.1770+1del variant is categorized as pathogenic for autosomal recessive COL6A2-related myopathy.