chr12-48000019-G-T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001844.5(COL2A1):c.192C>A(p.Cys64*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C64C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001844.5 stop_gained
Scores
Clinical Significance
Conservation
Publications
- achondrogenesis type IIInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
- Kniest dysplasiaInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
- platyspondylic dysplasia, Torrance typeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- spondyloepimetaphyseal dysplasia, Strudwick typeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
- spondyloepiphyseal dysplasia congenitaInheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
- spondyloepiphyseal dysplasia with metatarsal shorteningInheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- spondylometaphyseal dysplasiaInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- spondyloperipheral dysplasiaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Stickler syndrome type 1Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Illumina, Orphanet, Genomics England PanelApp
- Stickler syndrome, type I, nonsyndromic ocularInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- avascular necrosis of femoral head, primary, 1Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Legg-Calve-Perthes diseaseInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
- mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritisInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
- otospondylomegaepiphyseal dysplasia, autosomal recessiveInheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
- spondyloepiphyseal dysplasia, Stanescu typeInheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- autosomal dominant rhegmatogenous retinal detachmentInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- dysspondyloenchondromatosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial avascular necrosis of femoral headInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hypochondrogenesisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- multiple epiphyseal dysplasia, Beighton typeInheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
- spondylometaphyseal dysplasia, Schmidt typeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- otospondylomegaepiphyseal dysplasiaInheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
- vitreoretinopathy with phalangeal epiphyseal dysplasiaInheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL2A1 | ENST00000380518.8 | c.192C>A | p.Cys64* | stop_gained | Exon 2 of 54 | 1 | NM_001844.5 | ENSP00000369889.3 | ||
COL2A1 | ENST00000337299.7 | c.86-1588C>A | intron_variant | Intron 1 of 52 | 1 | ENSP00000338213.6 | ||||
COL2A1 | ENST00000474996.6 | n.430C>A | non_coding_transcript_exon_variant | Exon 3 of 8 | 3 | |||||
COL2A1 | ENST00000490609.2 | n.425C>A | non_coding_transcript_exon_variant | Exon 2 of 2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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The C64X variant in the COL2A1 gene has been reported previously in individuals with a predominantly ocular form of Stickler syndrome characterized by myopia and retinal detachment with cataract, perivascular pigmentation, and peripapillary retinal pigmentary atrophy reported in some individuals (McAlinden et al., 2008; Edwards et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The C64X variant is not observed in large population cohorts (Lek et al., 2016). We interpret C64X as a pathogenic variant. -
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This sequence change creates a premature translational stop signal (p.Cys64*) in the COL2A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL2A1 are known to be pathogenic (PMID: 20179744). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Stickler syndrome (PMID: 17721977). ClinVar contains an entry for this variant (Variation ID: 17401). For these reasons, this variant has been classified as Pathogenic. -
COL2A1-related disorder Pathogenic:1
The COL2A1 c.192C>A variant is predicted to result in premature protein termination (p.Cys64*). This variant has been reported in two unrelated individual with Stickler syndrome who displayed only the ocular phenotypes (McAlinden et al. 2008. PubMed ID: 17721977). This variant has not been reported in the large population database gnomAD, indicating this variant is rare. Nonsense variants in COL2A1 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic. -
Stickler syndrome type 1 Pathogenic:1
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. Both inter and intra-familial variability have been reported (GeneReviews). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Although this variant does not lie within a splice region, minigene assays have demonstrated skipping of exon 2 (PMID: 17721977). However, nonsense-mediated decay has not been excluded. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least five unrelated probands with Sticker syndrome (MIM#108300), including a large family with eighteen affected individuals. In addition, this variant has been classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 17721977, 20513134, 22574936). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Stickler syndrome, type I, nonsyndromic ocular Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at