Submissions for variant NM_003036.4(SKI):c.1619C>T (p.Ala540Val) (rs764786977)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199881	SCV000250683	uncertain significance	not provided	2018-12-06	criteria provided, single submitter	clinical testing	p.Ala540Val (A540V) GCG>GTG: c.1619 C>T in exon 5 of the SKI gene (NM_003036.3) A variant of unknown significance has been identified in the SKI gene. The A540V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A540V variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, the A540V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, no missense mutations in nearby residues have been reported in association with Shprintzen-Goldberg syndrome, 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-PANCARD,TAAD
Invitae	RCV000548962	SCV000637285	uncertain significance	Shprintzen-Goldberg syndrome	2018-02-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 540 of the SKI protein (p.Ala540Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. The frequency data for this variant (rs764786977) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a SKI-related disease. ClinVar contains an entry for this variant (Variation ID: 213697). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000618408	SCV000739603	uncertain significance	Cardiovascular phenotype	2016-02-17	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence

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