Submissions for variant NM_001844.5(COL2A1):c.4316C>T (p.Thr1439Met)

gnomAD frequency: 0.00005  dbSNP: rs121912886

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190574	SCV000245593	likely pathogenic	Spondyloperipheral dysplasia	2014-09-15	criteria provided, single submitter	clinical testing	The Thr1439Met variant in COL2A1 has been reported as de novo in one individual with spondyloepiphyseal dysplasia congenita and was shown to segregate with disease in 2 affected sons* (Unger 2001). This variant was not identified in large population studies. Computational analyses (biochemical amino acid properties, conservation, PolyPhen2, and SIFT) suggest that the Thr1439Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, this variant is located near the 5' splice region. Computational tools do not suggest an impact to splicing, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the Thr1439Met variant is likely pathogenic for spondyloepiphyseal dysplasia congenita in an autosomal dominant manner.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000018928	SCV000923488	uncertain significance	Spondyloepiphyseal dysplasia congenita	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001299254	SCV001488338	uncertain significance	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1439 of the COL2A1 protein (p.Thr1439Met). This variant is present in population databases (rs121912886, gnomAD 0.06%). This missense change has been observed in individual(s) with retinitis pigmentosa and/or spondyloepiphyseal dysplasia congenita (PMID: 11746045, 32381255). It has also been observed to segregate with disease in related individuals. This variant is also known as T1370M. ClinVar contains an entry for this variant (Variation ID: 17385). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
OMIM	RCV000018928	SCV000039213	pathogenic	Spondyloepiphyseal dysplasia congenita	2001-11-22	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004734525	SCV005348644	uncertain significance	COL2A1-related disorder	2024-03-15	no assertion criteria provided	clinical testing	The COL2A1 c.4316C>T variant is predicted to result in the amino acid substitution p.Thr1439Met. This variant, also described as p.Thr1370Met, was reported to be de novo in an in an individual with spondyloepiphyseal dysplasia congenita; however, parentage is not known to have been confirmed (Unger et al. 2001. PubMed ID: 11746045). In this family, the variant segregate with disease among two offspring of the proband, one of which was affected by a second skeletal dysplasia. This variant was also found in an individual with Kneist dysplasia (Table 1, Barat-Houari et al. 2015. PubMed ID: 26626311) and in an individual with atypical Stickler syndrome and retinitis pigmentosa (Breazzano et al. 2020. PubMed ID: 32381255). This variant is reported in 0.058% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which is more common than expected for a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.