Submissions for variant NM_080680.3(COL11A2):c.1615C>T (p.Arg539Trp)

gnomAD frequency: 0.00162  dbSNP: rs145499142

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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).
Eurofins Ntd Llc (ga)	RCV000709864	SCV000226691	uncertain significance	not provided	2016-11-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000268570	SCV000462516	likely benign	Fibrochondrogenesis 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000305029	SCV000462517	likely benign	Otospondylomegaepiphyseal dysplasia, autosomal recessive	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000359665	SCV000462518	likely benign	Stickler Syndrome, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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, 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
Invitae	RCV000709864	SCV001728692	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039826	SCV002598986	uncertain significance	not specified	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: COL11A2 c.1615C>T (p.Arg539Trp) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 281734 control chromosomes (gnomAD), predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. c.1615C>T has been reported in the literature in 4 siblings with confirmed early onset osteoarthritis. However, it was also detected in one family member with no radiological evidence of osteoarthritis, and was absent from another family member with osteoarthritis (Jakkula_2005). Furthermore, the variant has been reported in individuals affected with nonsyndromic hearing loss and Stickler syndrome, without strong evidence of causality (Acke_2014, Sommen_2016). These reports do not provide unequivocal conclusions about association of the variant with COL11A2-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, three as likely benign, and two as benign. One of the submitters reports internal evidence of occurrence of the variant in seven individuals with hearing loss, four of which were found to have an alternate genetic etiology (SCV000063517.5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Center for Human Genetics Tuebingen	RCV000709864	SCV004701546	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	COL11A2: BS2
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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000709864	SCV001799975	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000709864	SCV001965807	likely benign	not provided		no assertion criteria provided	clinical testing