ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.1105G>T (p.Val369Leu) (rs368057493)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000716768 SCV000847611 uncertain significance History of neurodevelopmental disorder 2016-08-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000485828 SCV000569210 uncertain significance not provided 2017-11-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CNTNAP2 gene. The V369L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant isobserved in 3/126596 (0.002%) alleles from individuals of European background, in large population cohorts (Lek et al., 2016). The V369L variant is a conservative amino acid substitution, which is not likely to impact secondaryprotein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter 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 RCV000644708 SCV000766411 uncertain significance Pitt-Hopkins-like syndrome 1 2017-10-16 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 369 of the CNTNAP2 protein (p.Val369Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs368057493, ExAC 0.002%). This variant has been reported in the literature in a family affected with speech impairment, however, the variant does not segregate with the phenotype (PMID: 28440294) . ClinVar contains an entry for this variant (Variation ID: 420390). 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.

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