rs121912874

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_001844.5(COL2A1):c.2965C>T(p.Arg989Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,722 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COL2A1
NM_001844.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.76

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

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 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, 0.974

PP5

Variant 12-47978329-G-A is Pathogenic according to our data. Variant chr12-47978329-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47978329-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5 link	c.2965C>T	p.Arg989Cys	missense_variant	Exon 43 of 54	ENST00000380518.8	NP_001835.3	P02458-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL2A1	ENST00000380518.8 link	c.2965C>T	p.Arg989Cys	missense_variant	Exon 43 of 54	1	NM_001844.5	ENSP00000369889.3	P02458-2
COL2A1	ENST00000337299.7 link	c.2758C>T	p.Arg920Cys	missense_variant	Exon 42 of 53	1		ENSP00000338213.6	P02458-1
COL2A1	ENST00000493991.5 link	n.2051C>T		non_coding_transcript_exon_variant	Exon 26 of 37	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461722

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 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 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. -

Dec 27, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Spondyloepiphyseal dysplasia congenita

Pathogenic:4

Jan 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Suma Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spondyloperipheral dysplasia

Pathogenic:2

May 27, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spondyloperipheral dysplasia;C4225273:Spondyloepiphyseal dysplasia, Stanescu type

Pathogenic:1

Feb 20, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Achondrogenesis type II;C0265279:Kniest dysplasia;C0432214:Namaqualand hip dysplasia;C0796173:Spondyloperipheral dysplasia;C1442965:Legg-Calve-Perthes disease;C1835437:Platyspondylic dysplasia, Torrance type;C1836080:Stickler syndrome, type I, nonsyndromic ocular;C1836683:Spondyloepiphyseal dysplasia with metatarsal shortening;C1851536:Multiple epiphyseal dysplasia, Beighton type;C2020284:Stickler syndrome type 1;C2745959:Spondyloepiphyseal dysplasia congenita;C4225273:Spondyloepiphyseal dysplasia, Stanescu type;C4551562:Avascular necrosis of femoral head, primary, 1;C4759767:Spondylometaphyseal dysplasia

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.0

M;.

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.1

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.84

Loss of MoRF binding (P = 0.0135);.;

MVP

0.95

MPC

0.43

ClinPred

0.99

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.82

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: -3

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