Submissions for variant NM_001848.3(COL6A1):c.717+4A>G

gnomAD frequency: 0.00006  dbSNP: rs762867111

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725541	SCV000337615	likely pathogenic	not provided	2018-03-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000725541	SCV000582906	uncertain significance	not provided	2020-04-10	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32065942, 30564623, 32403337)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000653543	SCV000775424	uncertain significance	Bethlem myopathy 1A	2024-09-05	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the COL6A1 gene. It does not directly change the encoded amino acid sequence of the COL6A1 protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with clinical features of COL6A1-related conditions (PMID: 30564623, 32065942, 32403337, 32528171; internal data). ClinVar contains an entry for this variant (Variation ID: 284826). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000653543	SCV000803836	pathogenic	Bethlem myopathy 1A	2016-06-23	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000725541	SCV002501836	uncertain significance	not provided	2021-08-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725541	SCV003833819	uncertain significance	not provided	2019-07-24	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000725541	SCV005620568	uncertain significance	not provided	2024-06-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734929	SCV005360967	likely pathogenic	not specified	2024-08-27	no assertion criteria provided	clinical testing	The COL6A1 c.717+4A>G variant is predicted to interfere with splicing. This variant has been reported in the homozygous state in an individual with limb-girdle muscular dystrophy 1A (Table S7, Nallamilli et al. 2018. PubMed ID: 30564623), in the heterozygous state with another COL6A1 variant in patients with COL6-related myopathies (Zanoteli et al. 2020. PubMed ID: 32065942; Internal Data, PreventionGenetics), and in the heterozygous state in individuals with COL6-related myopathies where a second variant was not reported (Gonzalez-Quereda et al. 2020. PubMed ID: 32403337; Supplementary Table 4, Töpf et al 2020. PubMed ID: 32528171). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). However, the use of computer prediction programs is not equivalent to functional evidence. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (Zhang. 1998. PubMed ID: 9536098; Buratti et al. 2007. PubMed ID: 17576681). This variant has conflicting classifications listed in ClinVar ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/284826/). This variant was reported in 0.0030% of alleles in individuals of European (non-Finnish) ancestry in gnomAD. This variant is interpreted as likely pathogenic.