chr12-47975971-C-T

Variant names:

• chr12-47975971-C-T
• rs121912870
• NM_001844.5:c.3589G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001844.5(COL2A1):​c.3589G>A​(p.Gly1197Ser) variant causes a missense change. 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. G1197R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 6.16
• Publications: 6 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 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain 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 chr12-47975971-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1326882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.993
• PP5: Variant 12-47975971-C-T is Pathogenic according to our data. Variant chr12-47975971-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17361.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
COL2A1	NM_001844.5	c.3589G>A	p.Gly1197Ser	missense_variant	Exon 50 of 54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.3589G>A	p.Gly1197Ser	missense_variant	Exon 50 of 54	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.3382G>A	p.Gly1128Ser	missense_variant	Exon 49 of 53	1		ENSP00000338213.6
COL2A1	ENST00000546974.1	n.442G>A		non_coding_transcript_exon_variant	Exon 5 of 6	1
COL2A1	ENST00000493991.5	n.2675G>A		non_coding_transcript_exon_variant	Exon 33 of 37	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Nov 30, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1197 of the COL2A1 protein (p.Gly1197Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant spondyloepiphyseal dysplasia congenita or spondyloepimetaphyseal dysplasia (PMID: 1905723, 25604898, 26626311). In at least one individual the variant was observed to be de novo. This variant is also known as Gly997Ser. ClinVar contains an entry for this variant (Variation ID: 17361). 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 triple helix domain of COL2A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL2A1, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. -

Mar 02, 2016

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (Jovanovic et al., 2021); 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: 8423604, 34008892, 34007986, 33908178, 1905723, 15895462) -

Jul 03, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stickler syndrome type 1 Pathogenic:2

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL2A1 c.3589G>A (p.Gly1197Ser) variant has been reported in heterozygous state in affected individuals. Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease. This variant is novel (not in any individual) in the gnomad and in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Gly at position 1197 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Gly1197Ser in COL2A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

May 04, 2022

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spondyloepiphyseal dysplasia congenita Pathogenic:2

Jan 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.3589G>A (p.Gly1197Ser) in COL2A1 gene has been reported in heterozygous state in in individual(s) with autosomal dominant spondyloepiphyseal dysplasia congenita or spondyloepimetaphyseal dysplasia (Barat-Houari et al.). Experimental studies have shown that this missense occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (Shoulders MD, Raines RT). The p.Gly1197Ser variant is novel (not in any individuals) in gnomAD exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic.The amino acid Gly at position 1197 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly1197Ser in COL2A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Namaqualand hip dysplasia Pathogenic:1

Feb 02, 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. Missense variants affecting glycine residue exert dominant-negative effect and is commonly associated with spondyloepiphyseal dysplasia (SED) (PMID: 15895462). (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 glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0601 - Variant is located in the well-established functional collagen triple helical domain. The variant affects the glycine of the Gly-X-Y repeat in this domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least ten individuals with spondyloepiphyseal dysplasia or spondyloepiphyseal dysplasia congenita (ClinVar, PMIDs: 15895462, 25604898). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Inborn genetic diseases Pathogenic:1

Feb 06, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3589G>A (p.G1197S) alteration is located in exon 50 (coding exon 50) of the COL2A1 gene. This alteration results from a G to A substitution at nucleotide position 3589, causing the glycine (G) at amino acid position 1197 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in individual(s) with features consistent with COL2A1-related skeletal dysplasia (Nishimura, 2005; Barat-Houari, 2015; Terhal, 2015; Markova, 2022; Campbell, 2023). Other variant(s) at the same codon, c.3589G>C (p.G1197R) and c.3590G>C (p.G1197A), have been identified in individual(s) with features consistent with COL2A1-related skeletal dysplasia (Markova, 2022; MacCarrick, 2024). This amino acid position is well conserved in available vertebrate species. The p.G1197 amino acid is located within the triple-helical domain of the collagen type II alpha-1 protein chain, and affects one of the highly conserved glycine residues in the Gly-X-Y motif that make up this domain (Ramshaw, 1998). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Spondyloepimetaphyseal dysplasia, Strudwick type Pathogenic:1

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1, PM1, PM2, PP2, PP3, PP5 -

Type 2 collagenopathy Pathogenic:1

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Spondyloperipheral dysplasia Pathogenic:1

Feb 23, 2023

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. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017361). Different missense changes at the same codon (p.Gly1197Ala, p.Gly1197Arg) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000988359, VCV001326882). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Connective tissue disorder Pathogenic:1

Feb 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

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	0.82
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;.
PhyloP100		6.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;D
Vest4		0.97
MutPred		0.98		Gain of phosphorylation at G1197 (P = 0.0033);.;
MVP		0.99
MPC		0.31
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.89
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912870; hg19: chr12-48369754;