ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.104C>A (p.Pro35Gln) (rs397514589)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000033007 SCV000958945 likely pathogenic Shprintzen-Goldberg syndrome 2018-08-28 criteria provided, single submitter clinical testing This sequence change replaces proline with glutamine at codon 35 of the SKI protein (p.Pro35Gln). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and glutamine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed to be de novo in an individual affected with Shprintzen-Goldberg syndrome (PMID: 23103230). ClinVar contains an entry for this variant (Variation ID: 39785). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Pro35 amino acid residue in SKI. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 23023332, 23103230, 24736733, 24357594), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000033007 SCV000056786 pathogenic Shprintzen-Goldberg syndrome 2012-11-02 no assertion criteria provided literature only

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