Submissions for variant NM_001848.3(COL6A1):c.1056+1G>A

dbSNP: rs398123631

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079739	SCV000226084	pathogenic	not provided	2017-01-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000079739	SCV000329924	pathogenic	not provided	2018-10-30	criteria provided, single submitter	clinical testing	The c.1056+1 G>A pathogenic variant in the COL6A1 gene has been previously reported in multiple patients with COL6A1-related disorders (Lamande et al., 1999; Pan et al., 2003; Lucioli et al., 2005; Baker et al., 2007; Kawahara et al., 2008). Reported individuals did not have a second identifiable COL6A1 pathogenic variant, and c.1056+1 G>A was found to be de novo in one case (Pan et al., 2003). This variant destroys the canonical splice donor site of intron 14 and functional studies demonstrate that it results in the skipping of exon 14, leading to abnormal gene splicing (Pan et al., 2003; Baker et al., 2007). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000018714	SCV000656972	pathogenic	Bethlem myopathy 1A	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 14 of the COL6A1 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 COL6A1 are known to be disease-causing for autosomal recessive COL6A1-related conditions (PMID: 21280092, 20976770). However, certain variants affecting donor or acceptor splice sites in the triple helical domain of COL6A1 are expected to result in in-frame exon skipping and have been reported to cause autosomal dominant COL6A1-related conditions (PMID: 18366090). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal dominant Bethlem myopathy (PMID: 10419498, 12840783, 15955946, 17886299, 25749816). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17174). Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (PMID: 10419498, 12840783). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626814	SCV000747517	pathogenic	Sensorimotor neuropathy	2017-01-01	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813996	SCV001755526	pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000079739	SCV002017479	pathogenic	not provided	2022-05-20	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000018714	SCV002579076	likely pathogenic	Bethlem myopathy 1A	2022-06-21	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000018714	SCV003922371	pathogenic	Bethlem myopathy 1A	2023-05-02	criteria provided, single submitter	curation	The heterozygous c.1056+1G>A variant in COL6A1 was identified by our study in one individual with congenital myopathy. Trio exome analysis showed this variant to be de novo. The c.1056+1G>A variant in COL6A1 has been reported in 19 unrelated individuals with autosomal dominant COL6A1-related myopathy (PMID: 24271325, PMID: 29419890, PMID: 25749816, PMID: 15955946, PMID: 17886299, PMID: 10419498, PMID: 12840783) and segregated with disease in 18 affected relatives from six families (PMID: 25749816, PMID: 15955946). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was previously found to be de novo in three individuals with paternity and maternity confirmed (PMID: 12840783, PMID: 29419890) and was assumed de novo in one individual but maternity and paternity have not been confirmed (PMID: 15955946). This variant has also been reported in ClinVar (Variation ID: 17174) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. RT-PCR analysis performed on affected tissue shows evidence of altered splicing, with in-frame skipping of exon 14 (PMID: 17886299, PMID: 10419498). Two different nucleotide changes that also result in a splice donor variant at the same site, c.1056+1G>T and c.1056+1G>C, have been previously reported pathogenic (ClinVar Variation ID: 946468, 1322138), and the variant being assessed here, c.1056+1G>A, is predicted by SpliceAI to have a similar effect on splicing. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. There is an in-frame cryptic splice site 54 bases from the intron-exon boundary, providing evidence that this variant may delete 18 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. Heterozygous loss of function of the COL6A1 gene is an established disease mechanism in autosomal dominant COL6A1-related myopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant COL6A1-related myopathy. ACMG/AMP Criteria applied: PVS1_Moderate, PS1_Supporting, PS2, PS3_Moderate, PM2_Supporting, PM3_VeryStrong, PM6_Supporting, PP1_Strong (Richards 2015).
3billion	RCV000018714	SCV005905521	pathogenic	Bethlem myopathy 1A	2023-09-27	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017174 /PMID: 10419498). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000018714	SCV000038997	pathogenic	Bethlem myopathy 1A	2007-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000018714	SCV001519042	not provided	Bethlem myopathy 1A		no assertion provided	literature only	Common variant that results in exon 14 skipping
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000079739	SCV001808978	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000079739	SCV001924321	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000079739	SCV001930850	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000079739	SCV001954170	pathogenic	not provided		no assertion criteria provided	clinical testing