Submissions for variant NM_001844.5(COL2A1):c.2965C>T (p.Arg989Cys)

dbSNP: rs121912874

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478360	SCV000568538	pathogenic	not provided	2022-09-12	criteria provided, single submitter	clinical testing	Functional studies using an inducible expression system for expressing p.(R989C) showed that even a small amount of the R989C mutant collagen would induce aberrations in the cell/matrix systems (Jensen et al., 2011); Located in the triple helical domain, a region of the protein in which cysteine residues are typically excluded (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16155195, 9101290, 35250876, 25735649, 8325895, 21924244, 15895462, 7752132, 29354277, 21472893)
Fulgent Genetics, Fulgent Genetics	RCV000762895	SCV000893295	pathogenic	Achondrogenesis type II; Avascular necrosis of femoral head, primary, 1; Multiple epiphyseal dysplasia, Beighton type; Legg-Calve-Perthes disease; Kniest dysplasia; Namaqualand hip dysplasia; Spondyloperipheral dysplasia; Stickler syndrome type 1; Platyspondylic dysplasia, Torrance type; Spondylometaphyseal dysplasia; Spondyloepiphyseal dysplasia congenita; Spondyloepiphyseal dysplasia with metatarsal shortening; Stickler syndrome, type I, nonsyndromic ocular; Spondyloepiphyseal dysplasia, Stanescu type	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000995718	SCV001150043	pathogenic	Spondyloperipheral dysplasia	2019-05-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000478360	SCV001581179	pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 989 of the COL2A1 protein (p.Arg989Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant spondyloepiphyseal dysplasia congenita (PMID: 8325895, 21924244, 25735649). It has also been observed to segregate with disease in related individuals. This variant is also known as R789C. ClinVar contains an entry for this variant (Variation ID: 17366). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL2A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects COL2A1 function (PMID: 21472893). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000478360	SCV001832237	pathogenic	not provided	2017-12-27	criteria provided, single submitter	clinical testing
3billion	RCV005252114	SCV002058184	pathogenic	Spondyloperipheral dysplasia; Spondyloepiphyseal dysplasia, Stanescu type	2024-02-20	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.73 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017366 /PMID: 8325895 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 21924244, 25735649, 8325895). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 21924244). A different missense change at the same codon (p.Arg989Gly) has been reported to be associated with COL2A1 related disorder (PMID: 33908178). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV000478360	SCV002497588	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000995718	SCV002578929	pathogenic	Spondyloperipheral dysplasia	2022-06-14	criteria provided, single submitter	clinical testing
Suma Genomics	RCV000018910	SCV004037036	likely pathogenic	Spondyloepiphyseal dysplasia congenita		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000018910	SCV005049425	pathogenic	Spondyloepiphyseal dysplasia congenita	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000018910	SCV000039194	pathogenic	Spondyloepiphyseal dysplasia congenita	1997-01-01	no assertion criteria provided	literature only
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000018910	SCV002569961	pathogenic	Spondyloepiphyseal dysplasia congenita		no assertion criteria provided	clinical testing