ClinVar Miner

Submissions for variant NM_080680.3(COL11A2):c.966dup (p.Thr323fs) (rs748440351)

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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 RCV000592394 SCV000702400 pathogenic not provided 2016-10-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778790 SCV000915161 uncertain significance COL11A2-Related Disorders 2018-01-30 criteria provided, single submitter clinical testing The COL11A2 c.966dupC (p.Thr323HisfsTer19) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL 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 for this variant, it 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. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for COL11A2-related disorders.
GeneDx RCV000592394 SCV001167938 likely pathogenic not provided 2019-10-02 criteria provided, single submitter clinical testing Observed in homozygous state in several unrelated patients referred for genetic testing at GeneDx and in published literature (Vona et al., 2017; Sloan-Heggen et al., 2015) and not observed in homozygous state in controls; Variant has been observed heterozygous in a proband without hearing loss or skeletal limb abnormalities who also had pathogenic findings in another gene by exome sequencing, which were consistent with the proband's phenotype (ClinVar, EGL pers. communication); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Stop codon variants in COL11A2 may have either an autosomal dominant or autosomal recessive inheritance pattern and may be associated with a milder presentation in AD families (Vuoristo et al 2004, Sirko-Osadsa DA et al., 1998, Thompson et al. 2012, Kayserili et al. 2011, Temtamy et al. 2006, Melkoniemi et al. 2000); Exon skipping of Stop codon variants is reported to be involved in the AD forms where some partially functional mRNA is produced (Vuoristo et al. 2004); Observed in 0.012% (34/281618 alleles) in large population cohorts (Lek et al., 2016)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195605 SCV001366004 uncertain significance not specified 2019-08-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr323HisfsX19 variant in COL11A2 has been previously reported in 3 Iranian individuals with hearing loss who were homozygous for the variant. It should be noted that consanguinity was reported for 1 individual, and was likely present for the remaining 2 (Sloan-Heggen 2015, Vona 2017). It has been reported in ClinVar (Variation ID 497724). This variant has also been reported in 34/281618 of the total chromosomes by gnomAD, with the highest frequency of 0.019% (7/35422) in Latino chromosomes ( This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 323 and leads to a premature termination codon 19 amino acids downstream. However, this variant is present in an in-frame exon that is only present in 1 transcript of COL11A2. Therefore, the impact to the protein is uncertain. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PVS1_Moderate, PM2_Supporting, PM3_Supporting.
Center for Reproductive Medicine, Peking University Third Hospital RCV001257368 SCV001433894 likely pathogenic Heart, malformation of; Thickened nuchal skin fold; Cystic hygroma; Short long bone 2019-10-16 criteria provided, single submitter clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000592394 SCV001959051 likely pathogenic not provided no assertion criteria provided clinical testing

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