ClinVar Miner

Submissions for variant NM_001844.5(COL2A1):c.4148C>T (p.Thr1383Met) (rs138498898)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523016 SCV000617519 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL2A1 gene. The T1383M variant has been reported previously in a 40-year-old male with a history of bilateral hip pain and subsequent diagnosis of avascular necrosis of the femoral head (Kannu et al., 2011). This individual's niece, with a history of epiphyseal dysplasia, did not harbor any variants in the COL2A1 gene based on prior genetic testing (Kannu et al., 2011). The T1383M variant has also been reported in one Japanese individual with early-onset bilateral sensorineural hearing loss; however, additional clinical information was not provided (Miyagawa et al., 2013). The T1383M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).The T1383M variant 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. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved across species; methionine is the wild-type amino acid at this position in lamprey. Furthermore, the T1383M variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL2A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012).
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000022484 SCV000746882 likely pathogenic Avascular necrosis of the head of femur 2017-12-18 criteria provided, single submitter clinical testing
OMIM RCV000022484 SCV000043773 pathogenic Avascular necrosis of the head of femur 2011-07-01 no assertion criteria provided literature only

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