ClinVar Miner

Submissions for variant NM_014159.6(SETD2):c.4027C>A (p.Gln1343Lys) (rs781672875)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523619 SCV000619184 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SETD2 gene. The Q1343K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Q1343K variant is observed in 1/66714 (0.001%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Q1343K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000552337 SCV000655742 uncertain significance Luscan-lumish syndrome 2017-06-24 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 1343 of the SETD2 protein (p.Gln1343Lys). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and lysine. This variant is present in population databases (rs781672875, ExAC 0.001%). This variant has not been reported in the literature in individuals with a SETD2-related disease. 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, this variant has uncertain impact on SETD2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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