Submissions for variant NM_001849.4(COL6A2):c.1461del (p.Ser488fs)

gnomAD frequency: 0.00003  dbSNP: rs398123645

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000599098	SCV000226758	pathogenic	not provided	2013-10-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000599098	SCV000710217	pathogenic	not provided	2022-03-22	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001231224	SCV001403737	pathogenic	Bethlem myopathy 1A	2023-11-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser488Leufs*57) 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 is present in population databases (rs398123645, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 93907). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002515767	SCV003761242	pathogenic	Ullrich congenital muscular dystrophy 1A	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Ser488LeuTerfs57 variant in COL6A2 was identified by our study, in the compound heterozygous state with a pathogenic variant (​​ClinVar Variation ID: 265506), in one individual with congenital myopathy. Trio exome analysis revealed that this variant was in trans with a pathogenic variant (​​ClinVar Variation ID: 265506). The p.Ser488LeuTerfs57 variant in COL6A2 has not been previously identified in individuals with autosomal recessive Ullrich congenital muscular dystrophy but has been identified in 0.003% (2/68040) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs398123645). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 93907) and has been interpreted as pathogenic by Eurofins NTD LLC, GeneDx, and Invitae. The affected individual identified by our study was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Ser488LeuTerfs57 variant is pathogenic. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 488 and leads to a premature termination codon 57 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the COL6A2 gene is an established disease mechanism in autosomal recessive Ullrich congenital muscular dystrophy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Ullrich congenital muscular dystrophy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015).