rs121912876
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001844.5(COL2A1):c.823C>T(p.Arg275Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R275H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001844.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL2A1 | NM_001844.5 | c.823C>T | p.Arg275Cys | missense_variant | 13/54 | ENST00000380518.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL2A1 | ENST00000380518.8 | c.823C>T | p.Arg275Cys | missense_variant | 13/54 | 1 | NM_001844.5 | P1 | |
COL2A1 | ENST00000337299.7 | c.616C>T | p.Arg206Cys | missense_variant | 12/53 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 275 of the COL2A1 protein (p.Arg275Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant COL2A1-related conditions (PMID: 8244341, 32071555). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg75Cys. ClinVar contains an entry for this variant (Variation ID: 17368). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2022 | 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; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 17368); This variant is associated with the following publications: (PMID: 21990059, 31633310, 31894489, 7757086, 16755660, 23928235, 23448908, 17726487, 31711313, 26183434, 15593085, 32071555, 31758797, 27234559, 28334714, 21204228, 26443184, 8877930, 26691295, 27523816, 16155195, 22791362, 21438135, 29738498, 25735649, 19433093, 21356074, 21472893, 18553548, 19764028, 21332586, 18383211, 8244341, 7738948, 8024616, 33706891, 30363003) - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 30, 2019 | - - |
Spondyloepiphyseal dysplasia with metatarsal shortening Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 22, 2022 | - - |
Acetabular dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Rheumatology and Immunology Department, Shandong Provincial Hospital Affiliated to Shandong First Medicial University | - | - - |
Achondrogenesis type II Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 20, 2023 | Variant summary: COL2A1 c.823C>T (p.Arg275Cys), also referred to by the legacy name Arg75Cys in the literature, results in a non-conservative amino acid change located in the collagen triple helix repeat region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250954 control chromosomes (gnomAD). c.823C>T has been reported in the literature in multiple individuals affected with Czech Dysplasia from geographically distinct families where it has been found to segregate with the disease phenotype in an autosomal dominant, fully penetrant pattern of inheritance (e.g. Carlson_2006, Tzschach_2008, Matsui_2009). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16755660, 19764028, 18553548). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Stickler syndrome type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at