ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.1943C>T (p.Thr648Met) (rs534215627)

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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 RCV000717811 SCV000848671 uncertain significance History of neurodevelopmental disorder 2017-01-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000187196 SCV000240776 uncertain significance not provided 2018-12-31 criteria provided, single submitter clinical testing p.Thr648Met (ACG>ATG): c.1943 C>T in exon 13 of the CNTNAP2 gene (NM_014141.5). The Thr648Met missense change in the CNTNAP2 has been reported as a non-synonymous somatic mutation in a prostate cancer tumor and is published in the COSMIC database (Grasso et al., 2012). It was not observed in approximately 6,500 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 variant is a non-conservative amino acid substitution of a polar Threonine residue with a non-polar Methionine residue. It alters a conserved position in the fibrinogen c-terminal domain. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Thr648Met is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000556826 SCV000645088 uncertain significance Pitt-Hopkins-like syndrome 1 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 648 of the CNTNAP2 protein (p.Thr648Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs534215627, ExAC 0.04%). This variant has not been reported in the literature in individuals with CNTNAP2-related disease. ClinVar contains an entry for this variant (Variation ID: 205253). 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: "Benign"; Align-GVGD: "Class C0"). 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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