ClinVar Miner

Submissions for variant NM_014846.4(WASHC5):c.2086G>A (p.Gly696Ser) (rs1060502725)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000490087 SCV000576857 uncertain significance not provided 2017-04-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KIAA0196 gene. The G696S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G696S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G696S 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a missense variant at the same residues (G696A) has been reported in the Human Gene Mutation Database in association with spastic paraplegia (Stenson et al., 2014). However, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000463139 SCV000550573 uncertain significance Dandy-Walker like malformation with atrioventricular septal defect; Spastic paraplegia 8 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 696 of the WASHC5 protein (p.Gly696Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a WASHC5-related disease.  However, a different substitution of the same amino acid (p.Gly696Ala) has been reported to segregate with spastic paraplegia in one family (PMID: 23455931). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It is not expected to cause disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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