ClinVar Miner

Submissions for variant NM_080679.2(COL11A2):c.1294C>T (p.Arg432Trp) (rs145499142)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039826 SCV000063517 likely benign not specified 2017-05-04 criteria provided, single submitter clinical testing p.Arg539Trp in exon 17 of COL11A2: This variant is not expected to have clinical significance because it has been identified in 0.2% (250/126012) European chrom osomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs145499142). Although it has been reported in one individual with Stickler syndrome and seven individuals with hearing los s (Acke 2014, LMM data), four of these individuals were found to have an alterna te genetic etiology. Furthermore, the variant was identified in one family with early onset osteoarthritis, but one affected family member was negative for the variant and one individual who carried the variant did not have disease (Jakkul a 2005).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000709864 SCV000226691 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000268570 SCV000462516 likely benign Fibrochondrogenesis 1 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000305029 SCV000462517 likely benign Otospondylomegaepiphyseal dysplasia, autosomal recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000359665 SCV000462518 likely benign Stickler Syndrome, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000265037 SCV000462519 likely benign Nonsyndromic Hearing Loss, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000319689 SCV000462520 likely benign Otospondylomegaepiphyseal dysplasia, autosomal dominant 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000039826 SCV000589684 uncertain significance not specified 2017-05-31 criteria provided, single submitter clinical testing A published variant of uncertain significance has been identified in the COL11A2 gene. The R539W variant was first reported in a 38-year-old Finnish individual with early-onset osteoarthritis (OA) and segregated with OA in three affected relatives (Jakkula et al., 2005). However, in this same family, R539W was found in a 45-year-old relative without OA and was absent from a 65-year-old relative with OA, although the age of onset in this relative was reportedly much later than other affected relatives (Jakkula et al., 2005). The R539W variant has also been reported in one Belgian individual with type 3 Stickler syndrome who had hearing loss and both a personal and family history of skeletal features of this condition (Acke et al., 2014); however, no segregation studies were described. More recently, this variant, reported as R453W due to the use of an alternate transcript, was identified in at least one Western European individual with presumed autosomal recessive non-syndromic hearing loss (Sommen et al., 2016), although further clinical or segregation data was not available. The R539W variant was observed at a frequency of approximately 0.16-0.28% of alleles from individuals of European ancestry, including one homozygous individual, in the NHLBI Exome Sequencing Project and Exome Aggregation Consortium, indicating it may be a rare benign variant in this population (Lek et al., 2016; Exome Variant Server). Nevertheless, R539W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Center for Human Genetics, Inc RCV000659336 SCV000781147 uncertain significance Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
Mendelics RCV000305029 SCV001137091 benign Otospondylomegaepiphyseal dysplasia, autosomal recessive 2019-05-28 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000709864 SCV000840199 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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