12-47982886-G-A
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001844.5(COL2A1):c.2155C>T(p.Arg719Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R719H) 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.2155C>T | p.Arg719Cys | missense_variant | 33/54 | ENST00000380518.8 | |
LOC105369752 | XR_944910.2 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL2A1 | ENST00000380518.8 | c.2155C>T | p.Arg719Cys | missense_variant | 33/54 | 1 | NM_001844.5 | P1 | |
COL2A1 | ENST00000337299.7 | c.1948C>T | p.Arg650Cys | missense_variant | 32/53 | 1 | |||
COL2A1 | ENST00000483376.1 | n.333C>T | non_coding_transcript_exon_variant | 4/8 | 5 | ||||
COL2A1 | ENST00000493991.5 | n.1079C>T | non_coding_transcript_exon_variant | 16/37 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460594Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726614
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
Namaqualand hip dysplasia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Zankl Lab, University of Sydney | Mar 15, 2023 | This variant (sometimes referred to as p.Arg519Cys in older literature) is very rare in the general population and has been identified in several other families with a similar phenotype (PMID: 16155195, 1975693, 1985108, 26443184). Type II collagen is a major constituent of articular cartilage. The variant leads to substitution of an Arginine with a Cysteine molecule in the triple helix domain of type II collagen. Functional studies suggest that this leads to abnormal assembly of type II collagen fibrils (PMID: 10372559). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 27, 2023 | This missense change has been observed in individual(s) with autosomal dominant osteoarthritis with mild chondrodysplasia or early-onset osteoarthritis (PMID: 1975693, 1985108, 26443184). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. 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: 17353). This variant is also known as p.Arg519Cys. This variant is present in population databases (rs121912865, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 719 of the COL2A1 protein (p.Arg719Cys). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (HGMD); Also known as p.Arg519Cys; This variant is associated with the following publications: (PMID: 37334733, 36142745, 32071555, 11708863, 26443184, 1985108, 37443051, 36682125, 32510848, 1975693, 32901917) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at