ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.136G>A (p.Val46Met) (rs137924687)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720498 SCV000851375 uncertain significance History of neurodevelopmental disorder 2017-12-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724579 SCV000227423 uncertain significance not provided 2015-03-03 criteria provided, single submitter clinical testing
GeneDx RCV000724579 SCV000240744 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing The V46M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V46M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V46M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000644725 SCV000766428 uncertain significance Pitt-Hopkins-like syndrome 1 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 46 of the CNTNAP2 protein (p.Val46Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs137924687, ExAC 0.1%). This variant has not been reported in the literature in individuals with CNTNAP2-related disease. ClinVar contains an entry for this variant (Variation ID: 195292). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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