Submissions for variant NM_004369.4(COL6A3):c.6354+1G>A

dbSNP: rs886042883

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000578834	SCV000338903	pathogenic	not provided	2018-01-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000319175	SCV000657374	pathogenic	Bethlem myopathy 1A	2023-09-21	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change affects a donor splice site in intron 19 of the COL6A3 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 COL6A3 are known to be disease-causing for autosomal recessive COL6A3-related conditions (PMID: 21280092, 20976770). However, certain variants affecting donor or acceptor splice sites in the triple helical domain of COL6A3 are expected to result in in-frame exon skipping and have been reported to cause autosomal dominant COL6A3-related conditions (PMID: 18366090). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Bethlem myopathy (PMID: 28688748; Invitae). ClinVar contains an entry for this variant (Variation ID: 285748). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000578834	SCV000681255	pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing	Observed in the heterozygous state in one patient with Bethlem myopathy in published literature; however, no further phenotypic information was provided (PMID: 28688748); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 30564623, 28688748, Farkosh2021[Case_Report])
Ambry Genetics	RCV000622451	SCV000742627	likely pathogenic	Inborn genetic diseases	2021-02-10	criteria provided, single submitter	clinical testing	The c.6354+1G>A intronic variant results from a G to A substitution one nucleotide after exon 19 (coding exon 18) of the COL6A3 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function (Ambry internal data). Based on the supporting evidence, this variant is expected to be causative of autosomal dominant muscular dystrophy; however, its clinical significance for autosomal recessive disease is unclear. Based on data from the Genome Aggregation Database (gnomAD), the COL6A3 c.6354+1G>A alteration was not observed, with coverage at this position. In a cohort of patients with congenital muscular dystrophy, one individual was reported to be heteroyzgous for this alteration (Sframeli, 2017). In addition, this alteration segregated with autosomal dominant disease in one family (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. The c.6354+1G>A alteration is located within the triple-helical domain of the collagen alpha-3(VI) chain and is predicted to impact a number of highly conserved glycine residues in the Gly-X-Y motif that make up this domain (Ramshaw, 1998). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic.
Revvity Omics, Revvity	RCV000578834	SCV002019673	pathogenic	not provided	2020-12-19	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV001249572	SCV001423541	not provided	Bethlem myopathy 1A; Ullrich congenital muscular dystrophy 1A		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported on 12-13-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.