rs121912884

Positions:

chr12-47985575-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong

The ENST00000380518.8(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
ENST00000380518.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 2.95

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in ENST00000380518.8

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL2A1. . Gene score misZ 3.2926 (greater than the threshold 3.09). Trascript score misZ 5.3726 (greater than threshold 3.09). GenCC has associacion of gene with spondylometaphyseal dysplasia, Schmidt type, spondyloepiphyseal dysplasia congenita, hypochondrogenesis, autosomal dominant rhegmatogenous retinal detachment, spondyloperipheral dysplasia, Kniest dysplasia, familial avascular necrosis of femoral head, spondylometaphyseal dysplasia, mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis, otospondylomegaepiphyseal dysplasia, autosomal recessive, multiple epiphyseal dysplasia, Beighton type, otospondylomegaepiphyseal dysplasia, Legg-Calve-Perthes disease, achondrogenesis type II, spondyloepiphyseal dysplasia, Stanescu type, platyspondylic dysplasia, Torrance type, Stickler syndrome type 1, dysspondyloenchondromatosis, vitreoretinopathy with phalangeal epiphyseal dysplasia, Stickler syndrome, type I, nonsyndromic ocular, avascular necrosis of femoral head, primary, 1, spondyloepiphyseal dysplasia with metatarsal shortening, spondyloepimetaphyseal dysplasia, Strudwick type.

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 [Likely_pathogenic]. Clinvar id is 17383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47985575-G-A is described in Lovd as [Pathogenic]. Variant chr12-47985575-G-A is described in Lovd as [Pathogenic]. Variant chr12-47985575-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5 linkuse as main transcript	c.1693C>T	p.Arg565Cys	missense_variant	26/54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8 linkuse as main transcript	c.1693C>T	p.Arg565Cys	missense_variant	26/54	1	NM_001844.5	ENSP00000369889	P1	P02458-2
COL2A1	ENST00000337299.7 linkuse as main transcript	c.1486C>T	p.Arg496Cys	missense_variant	25/53	1		ENSP00000338213		P02458-1
COL2A1	ENST00000493991.5 linkuse as main transcript	n.617C>T		non_coding_transcript_exon_variant	9/37	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Stickler syndrome type 1

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 22, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2000	- -
Likely pathogenic, criteria provided, single submitter	in vitro;research	Center of Medical Genetics, Central South University	Jul 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	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 -

COL2A1-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 20, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 06, 2020	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. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	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). 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) performed at Invitae indicates that this missense variant is not expected to disrupt COL2A1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2024	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) -

Stickler syndrome, type I, nonsyndromic ocular

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Miami Human Genetics, University Of Miami Miller School Of Medicine	May 09, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Mar 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.96

N;N

REVEL

Pathogenic

0.69

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.025

D;D

Polyphen

1.0

D;D

Vest4

0.84

MVP

0.95

MPC

1.8

ClinPred

0.96

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over