rs121912884

Variant names:

• chr12-47985575-G-A
• rs121912884
• NM_001844.5:c.1693C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-47985575-G-A
• chr12-47985575-G-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_001844.5(COL2A1):​c.1693C>T​(p.Arg565Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R565H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.95
• Publications: 16 publications found

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]

COL2A1 Gene-Disease associations (from GenCC):

• achondrogenesis type II

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Kniest dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• platyspondylic dysplasia, Torrance type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• spondyloepimetaphyseal dysplasia, Strudwick type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• spondyloepiphyseal dysplasia congenita

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• spondyloepiphyseal dysplasia with metatarsal shortening

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• spondylometaphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spondyloperipheral dysplasia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Stickler syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Illumina, Orphanet, Genomics England PanelApp
• Stickler syndrome, type I, nonsyndromic ocular

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• avascular necrosis of femoral head, primary, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Legg-Calve-Perthes disease

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• otospondylomegaepiphyseal dysplasia, autosomal recessive

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• spondyloepiphyseal dysplasia, Stanescu type

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant rhegmatogenous retinal detachment

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dysspondyloenchondromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial avascular necrosis of femoral head

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypochondrogenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• multiple epiphyseal dysplasia, Beighton type

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• spondylometaphyseal dysplasia, Schmidt type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• otospondylomegaepiphyseal dysplasia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• vitreoretinopathy with phalangeal epiphyseal dysplasia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001844.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the COL2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 376 curated pathogenic missense variants (we use a threshold of 10). The gene has 125 curated benign missense variants. Gene score misZ: 3.2926 (above the threshold of 3.09). Trascript score misZ: 5.3726 (above the threshold of 3.09). GenCC associations: The gene is linked to vitreoretinopathy with phalangeal epiphyseal dysplasia, Stickler syndrome, type I, nonsyndromic ocular, Kniest dysplasia, Stickler syndrome type 1, platyspondylic dysplasia, Torrance type, spondyloepiphyseal dysplasia with metatarsal shortening, spondyloperipheral dysplasia, spondyloepiphyseal dysplasia, Stanescu type, Legg-Calve-Perthes disease, achondrogenesis type II, spondyloepiphyseal dysplasia congenita, multiple epiphyseal dysplasia, Beighton type, mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis, autosomal dominant rhegmatogenous retinal detachment, spondylometaphyseal dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, familial avascular necrosis of femoral head, dysspondyloenchondromatosis, spondylometaphyseal dysplasia, Schmidt type, hypochondrogenesis, otospondylomegaepiphyseal dysplasia, autosomal recessive, otospondylomegaepiphyseal dysplasia, avascular necrosis of femoral head, primary, 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• PP5: Variant 12-47985575-G-A is Pathogenic according to our data. Variant chr12-47985575-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001844.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL2A1	NM_001844.5	MANE Select	c.1693C>T	p.Arg565Cys	missense	Exon 26 of 54	NP_001835.3
	COL2A1	NM_033150.3		c.1486C>T	p.Arg496Cys	missense	Exon 25 of 53	NP_149162.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL2A1	ENST00000380518.8	TSL:1 MANE Select	c.1693C>T	p.Arg565Cys	missense	Exon 26 of 54	ENSP00000369889.3
	COL2A1	ENST00000337299.7	TSL:1	c.1486C>T	p.Arg496Cys	missense	Exon 25 of 53	ENSP00000338213.6
	COL2A1	ENST00000493991.5	TSL:2	n.617C>T		non_coding_transcript_exon	Exon 9 of 37

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727206

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000264 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Stickler syndrome type 1 Pathogenic:4

Jul 01, 2022

Center of Medical Genetics, Central South University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: in vitro;research

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Loss of function is associated with Stickler Syndrome while missense variants affecting glycine residue exert dominant-negative effect and is commonly associated with spondyloepiphyseal dysplasia (PMIDs: 15895462, 27234559). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra- and inter-familial phenotypic variability and expressivity has been reported (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (highest allele count: 16 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated triple-helical region (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with Stickler (ClinVar, PMIDs: 16752401, 20179744). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Dec 22, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

COL2A1-related disorder Pathogenic:2

Feb 06, 2020

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL2A1 c.1693C>T (p.Arg565Cys) variant is a missense variant that has a well-documented association with Stickler syndrome. Across a selection of the available literature, this variant has been reported in a heterozygous state in at least eight affected individuals, including in a de novo state in one individual with confirmed parentage (Richards et al. 2000; Hoornaert et al. 2000; Wang et al. 2016; Zhou et al. 2018). This variant is not reported in the Genome Aggegation Database in a region of good sequencing coverage, indicating it is rare. The variant results in the substitution of a cysteine for an arginine in the X position of the Gly-X-Y repeat of the triple helical domain; this type of variant has been linked to ocular phenotypes. In addition to vitreous anomalies, myopia, and other ophthalmological anomalies, carriers of the p.Arg565Cys variant showed midface flattening, prominent eyes, low nasal bridge, and micrognathia. Mosaicism has been previously reported for COL2A1-related Stickler syndrome (Nagendran et al. 2012; Stevenson et al. 2012). Based on the cumulative evidence, the p.Arg565Cys variant is classified as pathogenic for COL2A1-related disorders.

Aug 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL2A1 c.1693C>T variant is predicted to result in the amino acid substitution p.Arg565Cys. This variant, which is also referred to as R365C based on legacy nomenclature, has been reported in multiple individuals with Stickler syndrome (see example: Richards et al. 2000. PubMed ID: 11007540; Wang et al. 2016. PubMed ID: 27390512; Choi et al. 2021. PubMed ID: 34680973). In one family with Stickler syndrome this variant segregated with disease in multiple affected members (Tian et al. 2024. PubMed ID: 38073514) and in at least one other patient this variant has been reported to have occurred de novo in the mosaic state (Muirhead et al. 2021. PubMed ID: 34737199). Some patients with early onset myopia have also been reported with this variant (Sun et al. 2015. PubMed ID: 26747767; Zhou et al. 2018. PubMed ID: 30181686). This variant impacts the amino acid that occurs in the X position of the important Gly-X-Y motif of the collagen molecule and has been experimentally shown to form aggregates in cells grown in culture and increase the endoplasmic reticulum stress response (Tian et al. 2024. PubMed ID: 38073514). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

not provided Pathogenic:2

Aug 12, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Other missense variants that introduce a cysteine residue in the triple helical domain have been reported in association with COL2A1-related conditions (HGMD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26443184, 18309338, 36460718, 36729443, 32039712, 38073514, 11007540, 20179744, 27390512, 21204228, 16155195, 20513134, 16752401, 28283280, 30181686, 29453956, 26747767, 31758797, 32112773, 30653986, 32756486, 34737199, 34680973, 35473494)

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 565 of the COL2A1 protein (p.Arg565Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Stickler syndrome or early onset high myopia (PMID: 11007540, 26747767, 27390512, 29453956). In at least one individual the variant was observed to be de novo. This variant is also known as R365C. ClinVar contains an entry for this variant (Variation ID: 17383). 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 not expected to disrupt COL2A1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Stickler syndrome, type I, nonsyndromic ocular Pathogenic:2

May 09, 2024

Miami Human Genetics, University Of Miami Miller School Of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been previously reported as de novo in a similarly affected individual (PMID: 26747767, 27390512, 27390512, PS2_S). It has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 26747767, 27390512, 27390512, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.687, 3CNET: 0.905, PP3_P). A missense variant is a common mechanism associated with Stickler sydrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Achondrogenesis type II Pathogenic:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PP4,PP5.

Retinal dystrophy Pathogenic:1

Mar 06, 2019

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.96	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.95
MPC		1.8
ClinPred		0.96	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.80
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121912884; hg19: chr12-48379358; COSMIC: COSV61528818; COSMIC: COSV61528818;