ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1336C>T (p.Leu446Phe)

gnomAD frequency: 0.00002  dbSNP: rs1464178129
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000788960 SCV000928263 uncertain significance not provided 2019-03-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV002386369 SCV002694501 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-04-07 criteria provided, single submitter clinical testing The p.L446F variant (also known as c.1336C>T), located in coding exon 4 of the SKI gene, results from a C to T substitution at nucleotide position 1336. The leucine at codon 446 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV002536911 SCV003288426 uncertain significance Shprintzen-Goldberg syndrome 2023-06-04 criteria provided, single submitter clinical testing 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. 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 SKI protein function. ClinVar contains an entry for this variant (Variation ID: 636979). This variant has not been reported in the literature in individuals affected with SKI-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 446 of the SKI protein (p.Leu446Phe).

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