chr19-18785772-G-T
Variant summary
Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_StrongPM1PM2PP3_StrongPP5_Very_Strong
The NM_000095.3(COMP):c.1569C>A(p.Asn523Lys) variant causes a missense 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N523S) 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 24 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COMP | NM_000095.3 | c.1569C>A | p.Asn523Lys | missense_variant | 14/19 | ENST00000222271.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COMP | ENST00000222271.7 | c.1569C>A | p.Asn523Lys | missense_variant | 14/19 | 1 | NM_000095.3 | P1 | |
COMP | ENST00000542601.6 | c.1470C>A | p.Asn490Lys | missense_variant | 13/18 | 1 | |||
COMP | ENST00000425807.1 | c.1410C>A | p.Asn470Lys | missense_variant | 13/18 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2022 | 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 COMP protein function. ClinVar contains an entry for this variant (Variation ID: 432270). This missense change has been observed in individual(s) with multiple epiphyseal dysplasia (PMID: 9021009, 17133256, 21922596). 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 asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 523 of the COMP protein (p.Asn523Lys). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2017 | The c.1569 C>A nucleotide substitution, resulting in the N523K amino acid change, has not been reported previously as a pathogenic or benign variant to our knowledge. However, a different nucleotide substitution (c.1569 C>G) that also results in the N523K missense substitution has been previously reported in association with multiple epiphyseal dysplasia (Ballo et al., 1997; Jackson et al., 2012). The N523K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N523K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (D518N, D518Y, D518H, D518G, T527A, T529A, T529I) have been reported in the Human Gene Mutation Database in association with COMP-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret N523K as a likely pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at