ClinVar Miner

Submissions for variant NM_001849.3(COL6A2):c.1336G>A (p.Asp446Asn) (rs535007570)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000232259 SCV000226456 likely benign not specified 2016-12-25 criteria provided, single submitter clinical testing
Center for Genetic Medicine Research,Children's National Medical Center RCV000232259 SCV000265832 uncertain significance not specified 2015-12-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000391113 SCV000436685 likely benign Collagen VI-related myopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000300525 SCV000436686 likely benign Myosclerosis 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000766827 SCV000618570 uncertain significance not provided 2018-09-06 criteria provided, single submitter clinical testing The D446N variant has been previously reported as a variant of uncertain clinical significance in an individual with limb-girdle muscular dystrophy (Punetha et al., 2016). The D446N variant is observed in 42/52,864 (0.08%) alleles from individuals of European background (Lek et al., 2016). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. This substitution occurs within the Gly-X-Y motif in the triple helical (TH) domain of collagen VI, a region that is well-conserved across species.
Invitae RCV000544905 SCV000657101 uncertain significance Bethlem myopathy 1 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 446 of the COL6A2 protein (p.Asp446Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs535007570, ExAC 0.1%). This variant has been reported in the heterozygous state in an individual affected with limb-girdle muscular dystrophy (LGMD) (PMID: 27854218) and in an unaffected control individual (PMID: 23040494). ClinVar contains an entry for this variant (Variation ID: 194621). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; 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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