17-72122794-C-G
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_000346.4(SOX9):c.507C>G(p.His169Gln) 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H169H) has been classified as Benign.
Frequency
Consequence
NM_000346.4 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000346.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SOX9 | NM_000346.4 | MANE Select | c.507C>G | p.His169Gln | missense | Exon 2 of 3 | NP_000337.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SOX9 | ENST00000245479.3 | TSL:1 MANE Select | c.507C>G | p.His169Gln | missense | Exon 2 of 3 | ENSP00000245479.2 | ||
| SOX9-AS1 | ENST00000414600.1 | TSL:3 | n.96+18891G>C | intron | N/A | ||||
| ENSG00000288605 | ENST00000628742.2 | TSL:5 | n.147-37749G>C | intron | N/A |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 36
GnomAD4 genome
ClinVar
Submissions by phenotype
Camptomelic dysplasia Pathogenic:4
The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 24038782). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.70 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with SOX9-related disorder (ClinVar ID: VCV000235914 /PMID: 24038782 /3billion dataset).The variant has been observed in at least two similarly affected unrelated individuals (PMID: 24038782). A different missense change at the same codon (p.His169Pro) has been reported to be associated with SOX9-related disorder (PMID: 19033726). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the SOX9 protein (p.His169Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of campomelic dysplasia (PMID: 24038782; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 235914). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOX9 protein function. Experimental studies have shown that this missense change affects SOX9 function (PMID: 24038782). This variant disrupts the p.His169 amino acid residue in SOX9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19033726, 24038782). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
not provided Pathogenic:2Uncertain:1
Reported in an individual with cleft palate, campomelia, scapular hypoplasia, scoliosis, short trunk, mild bowing of long bones of lower limbs, and hypoplastic patellae; the variant was inherited from the mother with mild skeletal findings (Matsushita et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect with reduced transactivation capacity of the protein (Matsushita et al., 2013); 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: 28965976, 19033726, 24038782)
Inborn genetic diseases Pathogenic:1
The alteration results in an amino acid change:_x000D_ _x000D_ The c.507C>G (p.H169Q) alteration is located in coding exon 2 of the SOX9 gene. This alteration results from a C to G substitution at nucleotide position 507, causing the histidine (H) at amino acid position 169 to be replaced by a glutamine (Q). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the SOX9 c.507C>G alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration was reported in a mother and son with an overlapping phenotype of mild campomelic dysplasia and small patella syndrome (Matsushita, 2013). The proband had cleft soft palate, developed scoliosis at age 7, and bilateral genu valgum deformities. He had a broad nasal bridge, disproportionate short trunk, asymmetric small scapulae, anteverted nares, and micrognathia. Skeletal surveys of the proband showed narrow iliac wings, defective iscio-pubic ossification, elongated femoral necks, hypoplastic lesser trochanter, and mild bowing of the long tubular bones of the lower limbs. The mother had proportionate normal stature, small patellae, and mild recurvatum of both knees (Matsushita, 2013). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.H169 amino acid is conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration:_x000D_ _x000D_ Using a luciferase assay in COS7 cells transiently expressing the mutation, Matsushita et al. (2013) found significantly reduced transactivation activity of the mutant protein at 46% of WT activity. They propose that the mutant retains some residual transactivation capacity for SOX9-responsive regulatory regions, explaining why some patients have relatively mild disease. The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.H169Q alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at