chr19-18785056-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000095.3(COMP):c.1754C>T(p.Thr585Met) 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. 12/20 in silico tools predict a damaging 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. T585K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000095.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COMP | NM_000095.3 | c.1754C>T | p.Thr585Met | missense_variant | 16/19 | ENST00000222271.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COMP | ENST00000222271.7 | c.1754C>T | p.Thr585Met | missense_variant | 16/19 | 1 | NM_000095.3 | P1 | |
COMP | ENST00000542601.6 | c.1655C>T | p.Thr552Met | missense_variant | 15/18 | 1 | |||
COMP | ENST00000425807.1 | c.1595C>T | p.Thr532Met | missense_variant | 15/18 | 2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2024 | Functional studies demonstrate that T585M mouse models exhibit slow growth, mildly shortened limbs, degeneration of articular cartilage, and reduced chondrocyte proliferation with cellular disorganization (PMID: 17588960); 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: 24595329, 23956175, 17570134, 24558358, 21922596, 9463320, 17588960) - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 08, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 06, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on COMP function (PMID: 17570134, 23956175). 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 COMP protein function. ClinVar contains an entry for this variant (Variation ID: 40995). This missense change has been observed in individuals with COMP-related skeletal dysplasia (PMID: 9463320, 11565064). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 585 of the COMP protein (p.Thr585Met). - |
Multiple epiphyseal dysplasia Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at