rs1565664095

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001844.5(COL2A1):​c.4453T>C​(p.Cys1485Arg) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1485G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

COL2A1
NM_001844.5 missense

Scores

17
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1

Conservation

PhyloP100: 9.32
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a domain Fibrillar collagen NC1 (size 234) in uniprot entity CO2A1_HUMAN there are 26 pathogenic changes around while only 1 benign (96%) in NM_001844.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
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, 0.994
PP5
Variant 12-47973418-A-G is Pathogenic according to our data. Variant chr12-47973418-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 597508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL2A1NM_001844.5 linkc.4453T>C p.Cys1485Arg missense_variant Exon 54 of 54 ENST00000380518.8 NP_001835.3 P02458-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL2A1ENST00000380518.8 linkc.4453T>C p.Cys1485Arg missense_variant Exon 54 of 54 1 NM_001844.5 ENSP00000369889.3 P02458-2
COL2A1ENST00000337299.7 linkc.4246T>C p.Cys1416Arg missense_variant Exon 53 of 53 1 ENSP00000338213.6 P02458-1
COL2A1ENST00000493991.5 linkn.3539T>C non_coding_transcript_exon_variant Exon 37 of 37 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Jun 18, 2018
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Sep 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1485 of the COL2A1 protein (p.Cys1485Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant COL2A1-related conditions (PMID: 31019026; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 597508). 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%. This variant disrupts the p.Cys1485 amino acid residue in COL2A1. Other variant(s) that disrupt this residue have been observed in individuals with COL2A1-related conditions (PMID: 15643621), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Spondyloepiphyseal dysplasia congenita Pathogenic:1
May 01, 2018
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is not present in the population SNP databases, and thus is predicted to be rare in the population. A different substitution at the same amino acid residue (c.4453T>G; p.Cys1485Gly) was previously reported as pathogenic in a patient with a platyspondylic lethal skeletal dysplasia, Torrance type (PMID: 15643621). Multiple in silico algorithms predict the p.Cys1485Arg change to be damaging. In addition, there are multiple reports of other pathogenic variants in this exon in the Human Gene Mutation Database (HGMD), as well as medical literature, to be associated with skeletal dysplasias (PMID: 15643621, 26626311, 15895462, 17163530), indicating that this C-terminus region of collagen type II is an important region for the protein function (PMID: 15643621). Based on the combined evidence, the c.4453T>C (p.Cys1485Arg) variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Uncertain
26
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.83
D;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.84
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
3.3
M;.
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-11
D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
1.0
MutPred
0.94
Gain of disorder (P = 2e-04);.;
MVP
0.97
MPC
0.56
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.98
gMVP
0.98

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

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

Other links and lift over

dbSNP: rs1565664095; hg19: chr12-48367201; API