Submissions for variant NM_001849.4(COL6A2):c.2978G>A (p.Arg993His)

gnomAD frequency: 0.00006  dbSNP: rs544436881

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000389290	SCV000436822	likely benign	Myosclerosis	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000278533	SCV000436823	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001343854	SCV001537872	uncertain significance	Bethlem myopathy 1A	2024-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 993 of the COL6A2 protein (p.Arg993His). This variant is present in population databases (rs544436881, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal dominant Bethlem myopathy (PMID: 34167565). ClinVar contains an entry for this variant (Variation ID: 340386). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL6A2 protein function with a negative predictive value of 80%. 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.
Revvity Omics, Revvity	RCV003137965	SCV003828605	uncertain significance	not provided	2020-10-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004735492	SCV005351277	uncertain significance	COL6A2-related disorder	2024-03-11	no assertion criteria provided	clinical testing	The COL6A2 c.2978G>A variant is predicted to result in the amino acid substitution p.Arg993His. This variant was reported to occur de novo in an individual with Bethlem myopathy (Inoue et al 2021. PubMed ID: 34167565). However, this variant is also reported in 0.020% of alleles in individuals of South Asian descent in gnomAD and may be too common for an autosomal dominant, pathogenic variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.