Submissions for variant NM_004369.4(COL6A3):c.4510C>T (p.Arg1504Trp)

dbSNP: rs144223596

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000487673	SCV000202552	uncertain significance	not provided	2018-03-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487673	SCV000575300	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000487673	SCV000618187	uncertain significance	not provided	2022-07-05	criteria provided, single submitter	clinical testing	Reported previously in the heterozygous state as a variant of uncertain significance in an individual with limb-girdle muscular dystrophy (Nallamilli et al., 2018); Reported along with a second COL6A3 variant in a patient with segmental and cervical dystonia and tremor; however, segregation information was not available (Kumar et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29411265, 30564623, 31731261)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528795	SCV000657317	likely benign	Bethlem myopathy 1A	2024-01-25	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000487673	SCV001143275	uncertain significance	not provided	2019-06-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001141518	SCV001301869	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.
Revvity Omics, Revvity	RCV000487673	SCV003834571	uncertain significance	not provided	2023-03-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586573	SCV005077594	uncertain significance	not specified	2024-04-29	criteria provided, single submitter	clinical testing	Variant summary: COL6A3 c.4510C>T (p.Arg1504Trp) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of 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 0.00088 in 1614116 control chromosomes in the gnomAD database, including 2 homozygotes. c.4510C>T has been reported in the literature in individuals affected with clinical features of COL6A3-related conditions (e.g. Kumar_2019, Meinke_2020, Nallamilli_2018). 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. The following publications have been ascertained in the context of this evaluation (PMID: 31731261, 31862442, 30564623). ClinVar contains an entry for this variant (Variation ID: 166943). Based on the evidence outlined above, the variant was classified as uncertain significance.