Submissions for variant NM_004369.4(COL6A3):c.4912G>A (p.Ala1638Thr)

gnomAD frequency: 0.00031  dbSNP: rs114322958

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001719926	SCV000196802	likely benign	not provided	2018-10-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24038877, 30687093)
Eurofins Ntd Llc (ga)	RCV000174100	SCV000225340	benign	not specified	2015-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000350868	SCV000428792	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.
Invitae	RCV000987066	SCV001018335	likely benign	Bethlem myopathy 1	2024-01-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000987066	SCV001136257	benign	Bethlem myopathy 1	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000174100	SCV002511683	likely benign	not specified	2022-04-19	criteria provided, single submitter	clinical testing	Variant summary: COL6A3 c.4912G>A (p.Ala1638Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 248592 control chromosomes, predominantly at a frequency of 0.0063 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is several-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in COL6A3 causing Ullrich Congenital Muscular Dystrophy 1 phenotype, strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.4912G>A has been reported in the literature in an individual affected with intermediate phenotype (Butterfield_2013). Furthermore, it was reported in individuals affected with neurological disease, ovarian cancer and Parkinson's disease (Wang_2019, Zhu_2020, Jin_2021), but it was also reported in healthy controls (Jin_2021). These reports do not provide unequivocal conclusions about association of the variant with Ullrich Congenital Muscular Dystrophy 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV001719926	SCV002544230	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	COL6A3: BS2
Department of Neurology, Xijing Hospital, Fourth Military Medical University	RCV002295283	SCV002553248	uncertain significance	Dystonia 27	2022-03-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945180	SCV004758520	likely benign	COL6A3-related condition	2019-12-09	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).