Submissions for variant NM_080680.3(COL11A2):c.2682G>A (p.Pro894=)

gnomAD frequency: 0.00068  dbSNP: rs113067047

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155071	SCV000204755	uncertain significance	not specified	2016-07-21	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Pro894Pro var iant in COL11A2 has been previously reported by our laboratory in the heterozygo us state in 1 individual with hearing loss who also had several additional varia nts in other genes related to hearing loss. This variant has been identified in 0.2% (14/9576) of African chromosomes and 12/65002 European Chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs11306 7047). Although this variant has been seen in the general population, its freque ncy is not high enough to rule out a pathogenic role. This variant does not alte r the amino acid sequence, but is located in the last base of the exon, which is part of the 5' splice region. Computational tools do not suggest an impact to s plicing. However, this information is not predictive enough to rule out pathogen icity. In summary, while the clinical significance of the p.Pro894Pro variant is uncertain, these data suggest it is more likely to be benign.
GeneDx	RCV001697115	SCV000717374	likely benign	not provided	2021-08-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001154198	SCV001315533	uncertain significance	Otospondylomegaepiphyseal dysplasia, autosomal recessive	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001154199	SCV001315535	uncertain significance	Otospondylomegaepiphyseal dysplasia, autosomal dominant	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001154200	SCV001315536	uncertain significance	Fibrochondrogenesis 2	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001697115	SCV002295904	uncertain significance	not provided	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change affects codon 894 of the COL11A2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL11A2 protein. This variant also falls at the last nucleotide of exon 36, which is part of the consensus splice site for this exon. This variant is present in population databases (rs113067047, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with COL11A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 178327). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
PreventionGenetics, part of Exact Sciences	RCV003975209	SCV004787088	likely benign	COL11A2-related disorder	2021-08-31	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).