Submissions for variant NM_003036.4(SKI):c.539C>T (p.Thr180Met) (rs863223722)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne	RCV000677641	SCV000803771	likely pathogenic	Shprintzen-Goldberg syndrome	2017-07-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000198523	SCV000250668	uncertain significance	not provided	2015-04-07	criteria provided, single submitter	clinical testing	p.Thr180Met (T180M) ACG>ATG: c.539 C>T in exon 1 of the SKI gene (NM_003036.3 )A variant of unknown significance has been identified in the SKI gene. The T180M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The T180M variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The T180M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported in association with SKI-related disorders, suggesting this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-1
Invitae	RCV000677641	SCV000957608	uncertain significance	Shprintzen-Goldberg syndrome	2018-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 180 of the SKI protein (p.Thr180Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SKI-related conditions. ClinVar contains an entry for this variant (Variation ID: 213684). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.