Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV001590017 | SCV001824840 | likely benign | not provided | 2020-03-16 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function |
Labcorp Genetics |
RCV001590017 | SCV002120038 | uncertain significance | not provided | 2024-01-14 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 585 of the COL9A2 protein (p.Val585Met). This variant is present in population databases (rs202153520, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with COL9A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1217758). 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 not expected to disrupt COL9A2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003487493 | SCV004241614 | uncertain significance | not specified | 2023-12-22 | criteria provided, single submitter | clinical testing | Variant summary: COL9A2 c.1753G>A (p.Val585Met) results in a conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.8e-05 in 230688 control chromosomes. To our knowledge, no occurrence of c.1753G>A in individuals affected with Epiphyseal dysplasia, multiple, 2 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=2; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. |
Victorian Clinical Genetics Services, |
RCV004785289 | SCV005399982 | uncertain significance | Stickler syndrome, type 5 | 2020-05-21 | criteria provided, single submitter | clinical testing | A heterozygous missense variant was identified, NM_001852.3(COL9A2):c.1753G>A in exon 30 of 32 of the COL9A2 gene. This substitution is predicted to create a minor amino acid change from valine to methionine at position 585 of the protein, NP_001843.1(COL9A2):p.(Val585Met). The valine at this position has low conservation (100 vertebrates, UCSC), but is located within the collagen triple helix repeat region. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0076% (20 heterozygotes, 0 homozygotes), but is enriched within the East Asian subpopulation (0.064%). An alternative residue change at the same location has been reported in the gnomAD database at a frequency of 0.39%, in the Jewish subpopulation. The variant has not been previously reported in a clinical testing setting. A different variant in the same codon resulting in a change to leucine has been reported as a VUS (LOVD). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |
Prevention |
RCV003399398 | SCV004104045 | uncertain significance | COL9A2-related disorder | 2024-03-27 | no assertion criteria provided | clinical testing | The COL9A2 c.1753G>A variant is predicted to result in the amino acid substitution p.Val585Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.064% of alleles in individuals of East Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |