ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1505C>T (p.Pro502Leu)

gnomAD frequency: 0.00001  dbSNP: rs1057520161
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000442707 SCV000511479 uncertain significance not provided 2016-11-21 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001062348 SCV001227143 uncertain significance Shprintzen-Goldberg syndrome 2024-03-22 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 502 of the SKI protein (p.Pro502Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SKI-related conditions. ClinVar contains an entry for this variant (Variation ID: 377202). 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) has been performed at Invitae 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 SKI protein function. 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.
Neuberg Centre For Genomic Medicine, NCGM RCV001062348 SCV005849506 uncertain significance Shprintzen-Goldberg syndrome criteria provided, single submitter clinical testing The missense c.1505C>T (p.Pro502Leu) variant in SKI gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Pro502Leu variant is present with allele frequency of 0.001% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Daamging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position in SKI is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 502 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).

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