rs121912882

chr12-47979534-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001844.5(COL2A1):c.2710C>T(p.Arg904Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R904H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.892

Genes affected

COL2A1 (HGNC:2200): (collagen type II alpha 1 chain) This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye. Mutations in this gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome type I, and spondyloepimetaphyseal dysplasia Strudwick type. In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia. There are two transcripts identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001844.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, COL2A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 12-47979534-G-A is Pathogenic according to our data. Variant chr12-47979534-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47979534-G-A is described in Lovd as [Pathogenic]. Variant chr12-47979534-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5	c.2710C>T	p.Arg904Cys	missense_variant	41/54	ENST00000380518.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8	c.2710C>T	p.Arg904Cys	missense_variant	41/54	1	NM_001844.5	P1
COL2A1	ENST00000337299.7	c.2503C>T	p.Arg835Cys	missense_variant	40/53	1
COL2A1	ENST00000493991.5	n.1796C>T		non_coding_transcript_exon_variant	24/37	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 07, 2020	The COL2A1 c.2710C>T; p.Arg904Cys variant (rs121912882), also known in traditional nomenclature as Arg704Cys, is reported in the literature in multiple individuals and families affected with Stickler syndrome type I or a related skeletal dysplasia (Ballo 1998, Barat-Houari 2016, Goyal 2016, Guo 2017, Hoornaert 2006, Nagendran 2012, Tomcíkova 2018, Wang 2016, Yang 2018). In one family, the variant was observed to segregate with disease (Ballo 1998), while in another family the variant was found in the proband but neither parent, suggesting a de novo origin (Guo 2016). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 904 is highly conserved, it occurs in the collagen triple helix domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Arginine-to-cysteine substitutions in the COL2A1 triple helix domain have been reported in association with a spectrum of skeletal phenotypes and can interfere with collagen stability, trafficking, or fibril formation (Hoornaert 2006). Based on available information, the p.Arg904Cys variant is considered to be pathogenic. References: Ballo R et al. Stickler-like syndrome due to a dominant negative mutation in the COL2A1 gene. Am J Med Genet. 1998 Oct 30;80(1):6-11. Barat-Houari M et al. The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype. Eur J Hum Genet. 2016 Jul;24(7):992-1000. Goyal M et al. Stickler Syndrome Type 1 with Short Stature and Atypical Ocular Manifestations. Case Rep Pediatr. 2016;2016:3198597. Guo L et al. Novel and recurrent COL11A1 and COL2A1 mutations in the Marshall-Stickler syndrome spectrum. Hum Genome Var. 2017 Oct 5;4:17040. Hoornaert KP et al. The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene. J Med Genet. 2006 May;43(5):406-13. Nagendran S et al. Somatic mosaicism and the phenotypic expression of COL2A1 mutations. Am J Med Genet A. 2012 May;158A(5):1204-7. Tomcíkova D et al. Marshall and stickler syndrome in one family. Cesk Slov Oftalmol. Winter 2018;74(3):108-111. Wang X et al. Mutation survey and genotype-phenotype analysis of COL2A1 and COL11A1 genes in 16 Chinese patients with Stickler syndrome. Mol Vis. 2016 Jun 23;22:697-704. Yang L et al. Pathogenic gene screening in 91 Chinese patients with short stature of unknown etiology with a targeted next-generation sequencing panel. BMC Med Genet. 2018 Dec 12;19(1):212. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 26, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 904 of the COL2A1 protein (p.Arg904Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Stickler syndrome (PMID: 9800905, 22496037, 27390512, 28018693, 28983407). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg704Cys. ClinVar contains an entry for this variant (Variation ID: 17379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL2A1 protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2022	Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; other missense variants that introduce a cysteine residue in the triple helical domain have been reported in association with COL2A1-related disorders (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: 28018693, 22496037, 30541462, 20513134, 20179744, 26626311, 26443184, 28983407, 27390512, 16155195, 29453956, 30650974, 32427345, 32037395, 9800905) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 22, 2017	- -

Multiple epiphyseal dysplasia, Beighton type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 30, 1998

- -

Myopia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.90		Loss of methylation at R904 (P = 0.0024);.;
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121912882; hg19: chr12-48373317; COSMIC: COSV61528961; COSMIC: COSV61528961;