ClinVar Miner

Submissions for variant NM_001848.2(COL6A1):c.667G>A (p.Asp223Asn) (rs199842980)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725579 SCV000337914 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing
GeneDx RCV000725579 SCV000583083 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL6A1 gene. The D223N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D223N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D223N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Integrated Genetics/Laboratory Corporation of America RCV001192867 SCV001361290 uncertain significance not specified 2019-10-01 criteria provided, single submitter clinical testing Variant summary: COL6A1 c.667G>A (p.Asp223Asn) results in a conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 155602 control chromosomes (gnomAD). The observed variant frequency is approximately 162-folds over the estimated maximal expected allele frequency for a pathogenic variant in COL6A1 causing Collagen Type VI-Related Disorders phenotype (4.8e-07). However, the frequency within the gnomAD cohort needs to be cautiously considered due to the cohort harboring individuals that could present with a COL6A1 phenotype since the age of onset of the syndromes associated with COL6A1 does vary. c.667G>A has been reported in the literature in individuals affected with suspected-LGMD with limited available information (ie, lack of co-occurrence and cosegregation data)(Nallamilli_2018). This report does not provide an unequivocal conclusion about association of the variant with Collagen Type VI-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Invitae RCV001240408 SCV001413346 uncertain significance Bethlem myopathy 1 2019-08-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 223 of the COL6A1 protein (p.Asp223Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals with clinical suspicion of limb-girdle muscular dystrophy (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 285060). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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.

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