12-47975971-C-T

Position:

• chr12-47975971-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 6.16

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• 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, 0.993
• PP5: Variant 12-47975971-C-T is Pathogenic according to our data. Variant chr12-47975971-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47975971-C-T is described in Lovd as [Pathogenic]. Variant chr12-47975971-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.3589G>A	p.Gly1197Ser	missense_variant	50/54	ENST00000380518.8	NP_001835.3

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2023	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 30, 2023	For these reasons, this variant has been classified as Pathogenic. 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). 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 expected to disrupt COL2A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17361). This variant is also known as Gly997Ser. 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 not present in population databases (gnomAD no frequency). 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -

Stickler syndrome type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Spondyloepiphyseal dysplasia congenita Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 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. 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 -

Type 2 collagenopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

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

Jul 01, 2023

- -

Spondyloepimetaphyseal dysplasia, Strudwick type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Oct 01, 2021

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

Spondyloperipheral dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Feb 23, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

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;.
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

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

Other links and lift over

dbSNP: rs121912870; hg19: chr12-48369754;