Submissions for variant NM_003036.4(SKI):c.1384C>G (p.Pro462Ala) (rs199797772)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467693	SCV000550379	uncertain significance	Shprintzen-Goldberg syndrome	2018-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline with alanine at codon 462 of the SKI protein (p.Pro462Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs199797772, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with SKI-related disease. ClinVar contains an entry for this variant (Variation ID: 409974). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics	RCV000621055	SCV000738430	uncertain significance	Cardiovascular phenotype	2016-07-12	criteria provided, single submitter	clinical testing	Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence;In silico models in agreement (benign)
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000658485	SCV000780253	likely benign	not provided	2018-01-01	criteria provided, single submitter	clinical testing