Submissions for variant NM_001848.3(COL6A1):c.2250+6G>C

gnomAD frequency: 0.00195  dbSNP: rs202212586

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000353872	SCV000338042	benign	not specified	2015-12-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000344297	SCV000436555	benign	Collagen 6-related myopathy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533751	SCV000657023	benign	Bethlem myopathy 1A	2025-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001311581	SCV000721746	likely benign	not provided	2021-03-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001311581	SCV001501814	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	COL6A1: BP4, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV001311581	SCV005207646	likely benign	not provided		criteria provided, single submitter	not provided
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000353872	SCV005885631	uncertain significance	not specified	2025-02-10	criteria provided, single submitter	clinical testing	Variant summary: COL6A1 c.2250+6G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0017 in 231380 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in COL6A1 causing Ullrich congenital muscular dystrophy 1 (0.0017 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2250+6G>C in individuals affected with Ullrich congenital muscular dystrophy 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 285149). Based on the evidence outlined above, the variant was classified as uncertain significance.