12-47978329-G-A
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001844.5(COL2A1):c.2965C>T(p.Arg989Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,722 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R989H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001844.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL2A1 | NM_001844.5 | c.2965C>T | p.Arg989Cys | missense_variant | 43/54 | ENST00000380518.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL2A1 | ENST00000380518.8 | c.2965C>T | p.Arg989Cys | missense_variant | 43/54 | 1 | NM_001844.5 | P1 | |
COL2A1 | ENST00000337299.7 | c.2758C>T | p.Arg920Cys | missense_variant | 42/53 | 1 | |||
COL2A1 | ENST00000493991.5 | n.2051C>T | non_coding_transcript_exon_variant | 26/37 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461722Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727184
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Spondyloepiphyseal dysplasia congenita Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1997 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017366, PMID:8325895, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 8325895, 21924244, 25735649, PS4_S). The variant was co-segregated with SED congenita, associated with COL2A1 gene in multiple affected family members (PMID: 21924244, PP1_P) .In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.947, 3CNET: 0.956, PP3_P). A missense variant is a common mechanism associated with SED congenita (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 27, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 989 of the COL2A1 protein (p.Arg989Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant spondyloepiphyseal dysplasia congenita (PMID: 8325895, 21924244, 25735649). It has also been observed to segregate with disease in related individuals. This variant is also known as R789C. ClinVar contains an entry for this variant (Variation ID: 17366). 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%. Experimental studies have shown that this missense change affects COL2A1 function (PMID: 21472893). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 12, 2022 | Functional studies using an inducible expression system for expressing p.(R989C) showed that even a small amount of the R989C mutant collagen would induce aberrations in the cell/matrix systems (Jensen et al., 2011); Located in the triple helical domain, a region of the protein in which cysteine residues are typically excluded (HGMD); 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: 16155195, 9101290, 35250876, 25735649, 8325895, 21924244, 15895462, 7752132, 29354277, 21472893) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2022 | - - |
Spondyloperipheral dysplasia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | May 27, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 14, 2022 | - - |
Achondrogenesis type II;C0265279:Kniest dysplasia;C0432214:Namaqualand hip dysplasia;C0796173:Spondyloperipheral dysplasia;C1442965:Legg-Calve-Perthes disease;C1835437:Platyspondylic dysplasia, Torrance type;C1836080:Stickler syndrome, type I, nonsyndromic ocular;C1836683:Spondyloepiphyseal dysplasia with metatarsal shortening;C1851536:Multiple epiphyseal dysplasia, Beighton type;C2020284:Stickler syndrome type 1;C2745959:Spondyloepiphyseal dysplasia congenita;C4225273:Spondyloepiphyseal dysplasia, Stanescu type;C4551562:Avascular necrosis of femoral head, primary, 1;C4759767:Spondylometaphyseal dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at